Opioid receptor ligands and methods of using and making same

ABSTRACT

This application describes compounds that can act as opioid receptor ligands, which compounds can be used in the treatment of, for example, pain and pain related disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. Non-Provisional application, which claimspriority to U.S. Provisional Application No. 61/596,808 filed Feb. 9,2012, and U.S. Provisional Application No. 61/466,809 filed Mar. 23,2011, each of which is incorporated herein by reference in its entirety.

FIELD

This application relates to a family of compounds acting as opioidreceptor ligands. Such compounds may provide therapeutic benefit in thetreatment of pain.

BACKGROUND

Opioid receptors (ORs) mediate the actions of morphine and morphine-likeopioids, including most clinical analgesics. Three molecularly andpharmacologically distinct opioid receptor types have been described: δ,κ and μ. Furthermore, each type is believed to have sub-types. All threeof these opioid receptor types appear to share the same functionalmechanisms at a cellular level. For example, activation of the opioidreceptors causes inhibition of adenylate cyclase, and recruitsβ-arrestin.

When therapeutic doses of morphine are given to patients with pain, thepatients report that the pain is less intense, less discomforting, orentirely gone. In addition to experiencing relief of distress, somepatients experience euphoria. However, when morphine in a selectedpain-relieving dose is given to a pain-free individual, the experienceis not always pleasant; nausea is common, and vomiting may also occur.Drowsiness, inability to concentrate, difficulty in mentation, apathy,lessened physical activity, reduced visual acuity, and lethargy mayensue.

There is a continuing need for new OR modulators to be used asanalgesics. There is a further need for OR agonists as analgesics havingreduced side effects. There is a further need for OR agonists asanalgesics having reduced side effects for the treatment of pain, immunedysfunction, inflammation, esophageal reflux, neurological andpsychiatric conditions, urological and reproductive conditions,medicaments for drug and alcohol abuse, agents for treating gastritisand diarrhea, cardiovascular agents and/or agents for the treatment ofrespiratory diseases and cough.

SUMMARY

This application describes opioid receptor (OR) ligands. It alsodescribes methods of modulating opioid receptor activity using thecompositions described herein. Certain compositions described herein actas opioid receptor agonists. Other compositions described herein act asopioid receptor antagonists.

This application describes compounds having the structure of Formula I:

In the structure above, variables A₁, A₂, A₃, A₄, A₅, B₁, B₂, B₃, B₄,B₅, and D₁ can be selected from the respective groups of chemicalmoieties later described. OR ligand derivatives and mimetics are alsoprovided. Also provided are processes for preparing these compounds.

This application also describes pharmaceutical compositions comprisingone or more compounds as described in this application apharmaceutically acceptable carrier. Naturally, the compounds describedherein can be employed in any form, such as a solid or solution (e.g.,aqueous solution) as is described further below. The compounds describedherein, for example, can be obtained and employed in a lyophilized formalone or with suitable additives.

Also provided are methods for treating pain and pain-related disorders.Such a method would comprise administering a therapeutically effectiveamount of one or more compounds described herein to a subjector subjectin need thereof.

DETAILED DESCRIPTION

This application describes a family of compounds, OR ligands, with aunique profile. The compounds described herein act as agonists orantagonists of opioid receptor (OR)-mediated signal transduction. Theligands of these receptors can be used to treat pathologies associatedwith ORs including pain and pain related disorders.

Compounds also comprise Formula I:

wherein: A₁ is null, CH₂, CHR₁, CR₁R₂, CH, CR₁, O, S, SO, SO₂, NH orNR₁; A₂ is null, CH₂, CHR₅, CR₅R₆, CH, CR₅, O, S, SO, SO₂, NH or NR₅; A₃is null, CH₂, CHR₇, CR₇R₈, O, S, SO, SO₂, NH, NR₇, CH or CR₇; A₄ isnull, CH₂, cycle of the formula C(CH₂)_(n), where n=2-5, CHR₉, CR₉R₁₀,O, S, SO, SO₂, NH, NR₉, CH or CR₉; and A₅ is null, CH₂, CHR₁₁, CR₁₁R₁₂,CH₂CH₂, CHR₁₁CH₂, CH₂CHR₁₁, CHR₁₁CHR₁₂, O, S, SO, SO₂, NH, NR₁₁, CH orCR₁₁.

No more than 2 out of 5 A_(a) (specifically A₁, A₂, A₃, A₄, A₅) can benull at the same time. The number of heteroatoms from A₁ to A₅ cannotexceed 2 at the same time, and O—O, S—O; S—S; S—N fragments in the ringstructure are excluded from this composition.

The ring containing A₁, A₂, A₃, A₄, A₅ and the carbon connected to D₁can be fused with another ring, such as benzene, pyridine, pyrimidine,furan, thiophene or pyridazine, but not limited to these examples, wherethe resulting bicycle is chemically stable and synthetically accessible.It is also understood that the above-mentioned fused rings could bemultiply substituted with cyano, halogen, alkyl, branched alkyl,halogenated alkyl, hydroxyl, alkyloxy, formyl, acetyl, amino,alkylamino, dialkylamino, mercaptanyl, alkylmercaptanyl, and other smallsubstitution groups. The bonds between A₁ and A₂, A₂ and A₃, A₃ and A₄,A₄ and A₅ can independently be a single bond or a double bond. The bondsbetween A₁ and A₂, A₂ and A₃, A₃ and A₄, A₄ and A₅ cannot be a doublebond at the same time.

A₂ and A₄ can be connected by a carbon bridge. Examples of such a bridgeinclude —CH₂—, and —CH₂CH₂—.

B₁ is CH₂, CHR₁₃, CR₁₃R₁₄, O, S, SO, SO₂, NH, NR₁₃, CR₁₃ or CO. B₂ isCH₂, CHR₁₅, CR₁₅R₁₆, CR₁₅ or CO. B₃ is H, alkyl, branched alkyl,halogenated alkyl, aryl, arylalkyl, alkylcarbonyl, branchedalkylcarbonyl, arylcarbonyl, alkoxycarbonyl, or alkylsulfonyl. B₄ isnull, C₁-C₆ alkyl, CH₂, CH₂CH₂, CHR₁₉, CR₁₉R₂₀ or CO. In someembodiments, when B₄ is an alkyl one or more of the hydrogens can bereplaced with a deuterium. B₅ is alkyl, branched alkyl, halogenatedalkyl, carbocycle-substituted alkyl, aryl, carbocycle or arylalkyl.

Aryl, carbocycle (non-aromatic)/heterocycle (non-aromatic with 1-3heteroatoms, including O, N, S) are either unsubstituted, or substitutedwith small substitution groups. Small substitution groups can be cyano,halogen, alkyl, branched alkyl, halogenated alkyl, hydroxyl, alkyloxy,amino, alkylamino, dialkylamino, mercaptanyl, alkylmercaptanyl,alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, alkylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,aryl, arylalkyl, carbocycle or carbocycle-alkyl. In some embodiments,the small substitution groups are selected from F, Cl, Br, CH₃, CH₂CH₃,CH₂F, CHF₂, CF₃, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, OH, OMe, OEt,O-iPr, OCF₃, NH₂, NHMe, NMe₂, methoxycarbonyl, methanesulfonyl, Ph,benzyl, MeSO₂, formyl, and acetyl.

Carbocycle may contain double bonds, but they should not be aromatic.

D₁ is an aryl group or a carbocycle.

An aryl group is either a monocyclic aromatic group or a bicyclicaromatic group, which may contain heteroatoms in the aromatic group(e.g. heteroaryl). The following structures are some examples ofrepresentative aryl groups, but the aryl groups are not limited to thoseexamples:

Carbocycle is either a monocyclic or a bicyclic non-aromatic ringsystem. The following structures are some examples of representativecarbocycle, but the carbocycle is not limited to those examples:

wherein X₁, and X₂ in the carbocycle examples are independently O, S, N,NH or NR₁₈.

The aryl groups can be independently mono or multiply substituted withcyano, halogen, alkyl, branched alkyl, halogenated alkyl, hydroxyl,alkyloxy, amino, alkylamino, dialkylamino, mercaptanyl,alkylmercaptanyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl,alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, aryl, arylalkyl, carbocycle, carbocycle-alkyl,and/or other small substitution groups. In some embodiments, the smallsubstitution groups are selected from F, Cl, Br, CH₃, CH₂CH₃, CH₂F,CHF₂, CF₃, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, OH, OMe, OEt,O-iPr, OCF₃, NH₂, NHMe, NMe₂, methoxycarbonyl, methanesulfonyl, Ph,benzyl, formyl, and acetyl.

D₁ is an aryl, or a carbocycle.

R₁, R₂, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₈, R₁₉,and R₂₀ are independently: cyano, halogen, hydroxyl, alkyloxy, alkyl,branched alkyl, halogenated alkyl, branched halogenated alkyl, aryl,arylalkyl, carbocycle, carbocycle-alkyl, alkylcarbonyl, branchedalkylcarbonyl, halogenated alkylcarbonyl, branched halogenatedalkylcarbonyl, arylcarbonyl or alkoxycarbonyl. In some embodiments, R₁,R₂, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₈, R₁₉, andR₂₀ are independently F, Cl, Br, CH₃, CH₂CH₃, CH₂F, CHF₂, CF₃, n-Pr,n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, OH, OMe, OEt, O-i-Pr,methoxycarbonyl, phenyl, benzyl, formyl or acetyl, whenever theresulting structure is stable.

R₁ and R₂, R₅ and R₆, R₇ and R₈, R₉ and R₁₀, R₁₁ and R₁₂, R₁₃ and R₁₄,R₁₅ and R₁₆, R₁₉ and R₂₀, or R₁₅ and R₁₉ can form a monocycle.

Me is methyl; Et is ethyl; i-Pr is i-propyl; t-Bu is t-butyl; Ph isphenyl.

In some embodiments, the following compounds can be excluded from thegenus of compounds:

1)2-[({2-[2-Ethyl-2-methyl-4-(4-methylphenyl)oxan-4-yl]ethyl}amino)methyl]phenol

2)2-[({2-[2-Ethyl-4-(4-fluorophenyl)-2-methyloxan-4-yl]ethyl}amino)methyl]phenol

3){2-[2,2-Dimethyl-4-(4-methylphenyl)oxan-4yl]ethyl}[(4-methoxyphenyl)methyl]amine

4){2-[(4S*,4R*)-2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl}[(1R)-1-phenylethyl]amine

5){2-[(4S*,4R*)-2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl}[(1S)-1-phenylethyl]amine

6) Benzyl({2-[2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl})amine

2-[({2-[2-Ethyl-4-(4-fluorophenyl)-2-methyloxan-4-yl]ethyl}amino)methyl]phenol

8) Benzyl[2-(2,2-dimethyl-4-phenyloxan-4-yl)ethyl]amine

9){2-[2-Ethyl-4-(4-fluorophenyl)-2-methyloxan-4-yl]ethyl}[(4-methoxyphenyl)methyl]amine

10)[(3,4-Dimethoxyphenyl)methyl]({2-[4-(4-fluorophenyl)-2,2-dimethyloxan-4-yl]ethyl})amine

11){2-[4-(4-Methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl}(1-phenylethyl)amine

12)[(4-Chlorophenyl)methyl]({2-[4-(4-methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl})amine

13)Benzyl({2-[2-ethyl-4-(2-methoxyphenyl)-2-methyloxan-4-yl]ethyl})amine

14)[(3,4-dimethoxyphenyl)methyl]({2-[2-ethyl-4-(2-methoxyphenyl)-2-methyloxan-4-yl]ethyl})amine

15)4-[({2-[4-(2-Methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl}amino)methyl]-N,N-dimethylaniline

16) Benzyl({2-[4-(4-fluorophenyl)-2,2-dimethyloxan-4-yl]ethyl})amine

17){2-[2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl}(1-phenylethyl)amine

18)[2-(2,2-Dimethyl-4-phenyloxan-4-yl)ethyl][(4-methoxyphenyl)methyl]amine

19){2-[4-(4-Fluorophenyl)-2,2-dimethyloxan-4-yl]ethyl}[(4-methoxyphenyl)methyl]amine

20)[(3,4-Dimethoxyphenyl)methyl][2-(2,2-dimethyl-4-phenyloxan-4-yl)ethyl]amine

This application also describes compounds having the structure ofFormula II-1 and II-2:

wherein A₂ is CH₂, CHR₅, CR₅R₆; A₄ is CH₂, CHR₉, CR₉R₁₀ or a cycle ofthe formula C(CH₂)_(n), where n=2-5.

Further R₅, R₆, R₉, and R₁₀ are independently CH₃, CH₂CH₃, CH₂F, CHF₂,CF₃, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, or phenyl. Further, R₅ andR₆, or R₉ and R₁₀ can form a monocyclic carbocycle.

A₂ and A₄ can be connected by a carbon bridge. This bridge can be —CH₂—or —CH₂CH₂—.

Further B₃ is selected from the following: H, alkyl, branched alkyl,aryl, arylalkyl, alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl,alkoxycarbonyl, and alkylsulfonyl. In some embodiments, B₃ is C₁-C₅alkyl. In some embodiments, B₃ is H.

Further B₄ is null, C₁-C₆ alkyl, CH₂, CH₂CH₂, CHR₁₉, CR₁₉R₂₀ or CO.Further, R₁₉ and R₂₀ can form a monocycle of the formula (CH₂)_(n),where n=2-4. B₅ is alkyl, branched alkyl, carbocycle,carbocycle-substituted alkyl, aryl or arylalkyl.

Further D₁ is an aryl. Examples of the aryl groups are shown above.

Each aryl group can be independently mono or multiply substituted withF, Cl, Br, CH₃, CH₂CH₃, CH₂F, CHF₂, CF₃, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr,t-Bu, CN, OH, OMe, OEt, O-iPr, OCF₃, NH₂, NHMe, NMe₂, methoxycarbonyl,Ph, benzyl, formyl, or acetyl. That is, each aryl group may be multiplysubstituted with the same substituent (i.e., 2 chloro groups) or just bemultiply substituted, albeit with different groups (e.g. an aryl groupwith 1 chloro and 1 methyl group would be considered multiplysubstituted).

This application also describes compounds having the structure ofFormula III:

wherein A₂ is CH₂, CHR₅ or CR₅R₆; A₄ is CH₂, CHR₉, CR₉R₁₀ or a cycle ofthe formula C(CH₂)_(n), where n=2-5.

Further R₅, R₆, R₉, and R₁₀ are independently CH₃, CH₂CH₃, CH₂F, CHF₂,CF₃, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, or phenyl. R₅ and R₆, or R₉and R₁₀ can form a monocyclic carbocycle.

A₂ and A₄ can be connected by a carbon bridge. The bridge can be —CH₂—or —CH₂CH₂—.

Further B₃ is selected from H, alkyl, branched alkyl, aryl, arylalkyl,alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl oralkylsulfonyl.

Further B₄ is null, C₁-C₆ alkyl, CH₂, CH₂CH₂, CHR₁₉, CR₁₉R₂₀ or CO.Further, R₁₉ and R₂₀ can form a monocycle of the formula (CH₂)_(n),where n=2-4. B₅ is alkyl, branched alkyl, carbocycle,carbocycle-substituted alkyl, aryl or arylalkyl.

Further D₁ is an aryl. Examples of the aryl groups are shown above.

The aryl groups can be mono or multiply substituted with F, Cl, Br, CH₃,CH₂CH₃, CH₂F, CHF₂, CF₃, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, OH,OMe, OEt, O-iPr, OCF₃, NH₂, NHMe, NMe₂, methoxycarbonyl, Ph, benzyl,formyl, or acetyl.

This application also describes compounds having the structure ofFormula IV-1, IV-2, or IV-3, V, or VI:

wherein R₂₁ and R₂₂ are, independently, H or CH₃; A₄ is CH₂, CR₉R₁₀ or acycle of the formula C(CH₂)_(n), where n=2-5.

Further R₉ and R₁₀ are independently CH₃ or CH₂CH₃.

Further B₃ is H, C₁-C₆ alkyl or branched alkyl.

Further B₄ is null, C₁-C₆ alkyl, CH₂, CH₂CH₂, or —CHCH₃.

B₅ is —(CH₂)_(n)CH₃, where n=2-3, —C(CH₃)₃, cyclohexyl, cyclopentyl,aryl or arylalkyl.

The aryl group can be selected from the list below:

Each aryl groups can be mono or multiply substituted with F, I, Cl, Br,CH₃, CN, OH, OMe, OEt, OCF₃, CF₃, or methanesulfonyl.

Further, in some embodiments, D₁ is a phenyl, 2-pyridyl, 3-pyridyl, or4-pyridyl which can be independently mono or multiply substituted withF, Cl, Br, OCF₃, CF₃, or CH₃.

This application also describes compounds having the structure ofFormula V-1, V-2, V-3, VI-1, VI-2, or VI-3:

wherein D₁ is an aryl; B₅ is an aryl or carbocycle.

In some embodiments, each aryl group is independently selected from thelist below:

In some embodiments, each aryl group is independently mono or multiplysubstituted. In some embodiments, each aryl group can be independentlymono or multiply substituted with I, F, Cl, Br, CH₃, CN, OH, OMe, OEt,OCF₃, CF₃, or methane sulfonyl. Further, in some embodiments, thecarbocycle is cyclohexyl, cyclohexenyl or cyclopentyl.

In some embodiments, D₁ is an optionally mono or multiply substitutedaryl. In some embodiments, B₅ is an optionally mono or multiplysubstituted aryl or carbocycle. In some embodiments, D₁ or B₅ isindependently selected from the group consisting of:

andwherein the carbocycle is cyclohexyl, cyclohexenyl or cyclopentyl.

In some embodiments, D₁ is optionally mono or multiply substitutedphenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl. In some embodiments, D₁ isoptionally substituted with one or more of F, Cl, Br, I, OCF₃, CH₃, andCF₃. In some embodiments, D₁ is not substituted.

In some embodiments, B₅ is optionally mono or multiply substituted

In some embodiments, B₅ is substituted with one or more of Cl, Br, F, I,OMe, CN, CH₃, methanesulfonyl, and CF₃. In some embodiments, B₅ issubstituted with two or more of Cl, Br, F, I, OMe, CN, CH₃, CF₃, andmethanesulfonyl, or a combination thereof. That is B₅ can have two ormore substituents but not all of the plurality of substituents needs tobe the same.

In some embodiments, compounds having structures of Formula VII-1,VII-2, or VII-3

are provided, wherein D₁ is an optionally substituted heteroaryl oraryl, B₃ is H or alkyl, B₅ is an optionally substituted aryl orheteroaryl, and R₂₆ and R₂₇ are each hydrogen or an isotope thereof. Insome embodiments, R₂₆ and R₂₇ are deuterium. In some embodiments, R₂₆ orR₂₇ are independently alkyl. In some embodiments, B₃ is C₁-C₅ alkyl.

In some embodiments, the compound has a structure of Formula VIII or anenantiomer thereof.

wherein D1 is an optionally substituted heteroaryl or aryl, B3 is H oralkyl, B5 is an optionally substituted aryl or heteroaryl, and R26 andR27 are each hydrogen or an isotope thereof. In some embodiments, R26and R27 are deuterium. In some embodiments, R26 or R27 are independentlyalkyl. A4 is as described herein. In some embodiments, B3 is C1-C5alkyl. In some embodiments, the enantiomer is the R or S enantiomer atthe carbon that is connected to D1.

In some embodiments, a compound has the structure of Formula IX or anenantiomer thereof

In some embodiments, the enantiomer is the R or S enantiomer at thecarbon that is connected to D₁.

In some embodiments, a compound has the structure of Formula X or anenantiomer thereof

In some embodiments, the enantiomer is the R or S enantiomer at thecarbon that is connected to D1.

In some embodiments of the structures described herein, D1 is anoptionally substituted pyridyl group or phenyl group. In someembodiments, D1 is an optionally substituted 2-pyridyl, 3-pyridyl, or4-pyridyl group or phenyl group. In some embodiments, D1 is optionallysubstituted with one or more of, H, OH, alkyl alcohol, halo, alkyl,amide, cyano, alkoxy, haloalkyl, or alkylsulfonyl. In some embodiments,D1 is optionally substituted with one or more of H, OH, Cl, Br, F, I,OMe, CN, CH₃, CF₃.

In some embodiments of the structures described herein, B₅ is anoptionally substituted thiophene group. In some embodiments, B₅ issubstituted with an alkoxy group. In some embodiments, B₅ is substitutedwith a C₁-C₅ alkoxy group. In some embodiments, B₅ is substituted with amethoxy group. In some embodiments, B₅ is

In some embodiments, B₅ is

wherein R₂₃, R₂₄, and R₃₀ are each independently null, H, OH, cycle,aryl, branched or unbranched alkyl alcohol, halo, branched or unbranchedalkyl, amide, cyano, alkoxy, haloalkyl, alkylsulfonyl, nitrite,alkylsulfanyl, and R₂₅ is H or alkyl. In some embodiments, R₂₃ and R₂₄together form a aryl or cycle that is attached to one or more of theatoms of B₅. R₂₃ R₂₄, and R₃₀ can also be further substituted. In someembodiments, R₂₃, R₂₄, and R₃₀ are each independently H, NH₂, OH, Cl,Br, F, I, OMe, CN, CH₃, phenyl, C₃-C₆ carbocycle, methanesulfonyl, CF₃,

wherein R₂₉ is H or an alkyl. In some embodiments, R₂₉ is a C₁-C₆ alkyl.In some embodiments, one of R₂₃, R₂₄, and R₃₀ is H. In some embodiments,at least one of R₂₃, R₂₄, and R₃₀ is H. In some embodiments, two of R₂₃,R₂₄, and R₃₀ are H.

The following compounds and others described herein have agonistactivity for OR mediated signal transduction:

-   [(4-chlorophenyl)methyl]({2-[4-(4-methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl})amine-   [(3,4-dimethoxyphenyl)methyl][2-(2,2-dimethyl-4-phenyloxan-4-yl)ethyl]amine-   2-[({2-[2-ethyl-2-methyl-4-(4-methylphenyl)oxan-4-yl]ethyl}amino)methyl]phenol-   [2-(2,2-dimethyl-4-phenyloxan-4-yl)ethyl][(2-fluorophenyl)methyl]amine-   4-[({2-[4-(2-methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl}amino)methyl]-N,N-dimethylaniline-   2-[({2-[2-ethyl-4-(4-fluorophenyl)-2-methyloxan-4-yl]ethyl}amino)methyl]phenol-   [(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine.

In some embodiments, compounds, such as the ones described herein areprovided. In some embodiments, a compound selected from the compoundsdescribed in the Examples is provided. The compounds can be used in anyof the methods described herein, including, but not limited to, treatingpain.

Thus, the application provides methods of generating agonist activity inOR mediated signal transduction through administration of one or more ofthe above recited compounds to a subject or subject in need thereof.

Various atoms in the compositions described herein can be isotopes thatoccur at lower frequency. Hydrogen can be replaced at any position inthe compositions described herein with deuterium. Optionally, hydrogencan also be replaced with tritium. Carbon (¹²C) can be replaced at anyposition in the compositions described herein with ¹³C or ¹⁴C. Nitrogen(¹⁴N) can be replaced with ¹⁵N. Oxygen (¹⁶O) can be replaced at anyposition in the compositions described herein with ¹⁷O or ¹⁸O, Sulfur(³²S) can be replaced at any position in the compositions describedherein with ³³S, ³⁴S or ³⁶S. Chlorine (³⁵Cl) can be replaced at anyposition in the compositions described herein with ³⁷Cl. Bromine (⁷⁹Br)can be replaced at any position in the compositions described hereinwith ⁸¹Br.

Selected compounds described herein are agonists and antagonists ofOpioid Receptors (ORs). The ability of the compounds to stimulate ORmediated signaling may be measured using any assay known in the art todetect OR mediated signaling or OR activity, or the absence of suchsignaling/activity. “OR activity” refers to the ability of an OR totransduce a signal. Such activity can be measured, e.g., in aheterologous cell, by coupling an OR (or a chimeric OR) to a downstreameffector such as adenylate cyclase.

A “natural ligand-induced activity” as used herein, refers to activationof the OR by a natural ligand of the OR. Activity can be assessed usingany number of endpoints to measure OR activity.

Generally, assays for testing compounds that modulate OR-mediated signaltransduction include the determination of any parameter that isindirectly or directly under the influence of a OR, e.g., a functional,physical, or chemical effect.

Samples or assays comprising ORs that are treated with a potentialactivator, inhibitor, or modulator are compared to control sampleswithout the inhibitor, activator, or modulator to examine the extent ofinhibition. Control samples (untreated with inhibitors) are assigned arelative OR activity value of 100%. Inhibition of an OR is achieved whenthe OR activity value relative to the control is about 80%, 50%, or 25%.Activation of an OR is achieved when the OR activity value relative tothe control (untreated with activators) is 110%, 150%, 200-500% (i.e.,two to five fold higher relative to the control) or, 1000-3000% orhigher.

The effects of the compounds upon the function of an OR can be measuredby examining any of the parameters described above. Any suitablephysiological change that affects OR activity can be used to assess theinfluence of a compound on the ORs and natural ligand-mediated ORactivity. When the functional consequences are determined using intactcells or animals, one can also measure a variety of effects such aschanges in intracellular second messengers such as cAMP.

Modulators of OR activity are tested using OR polypeptides as describedabove, either recombinant or naturally occurring. The protein can beisolated, expressed in a cell, expressed in a membrane derived from acell, expressed in tissue or in an animal. For example, neuronal cells,cells of the immune system, transformed cells, or membranes can be usedto test the GPCR polypeptides described above. Modulation is testedusing one of the in vitro or in vivo assays described herein. Signaltransduction can also be examined in vitro with soluble or solid statereactions, using a chimeric molecule such as an extracellular domain ofa receptor covalently linked to a heterologous signal transductiondomain, or a heterologous extracellular domain covalently linked to thetransmembrane and or cytoplasmic domain of a receptor. Furthermore,ligand-binding domains of the protein of interest can be used in vitroin soluble or solid state reactions to assay for ligand binding.

Ligand binding to an OR, a domain, or chimeric protein can be tested ina number of formats. Binding can be performed in solution, in a bilayermembrane, attached to a solid phase, in a lipid monolayer, or invesicles. Typically, in an assay described herein, the binding of thenatural ligand to its receptor is measured in the presence of acandidate modulator. Alternatively, the binding of the candidatemodulator may be measured in the presence of the natural ligand. Often,competitive assays that measure the ability of a compound to competewith binding of the natural ligand to the receptor are used. Binding canbe tested by measuring, e.g., changes in spectroscopic characteristics(e.g., fluorescence, absorbance, refractive index), hydrodynamic (e.g.,shape) changes, or changes in chromatographic or solubility properties.

Modulators may also be identified using assays involving β-arrestinrecruitment. β-arrestin serves as a regulatory protein that isdistributed throughout the cytoplasm in unactivated cells. Ligandbinding to an appropriate OR is associated with redistribution ofβ-arrestin from the cytoplasm to the cell surface, where it associateswith the OR. Thus, receptor activation and the effect of candidatemodulators on ligand-induced receptor activation, can be assessed bymonitoring β-arrestin recruitment to the cell surface. This isfrequently performed by transfecting a labeled β-arrestin fusion protein(e.g., β-arrestin-green fluorescent protein (GFP)) into cells andmonitoring its distribution using confocal microscopy (see, e.g.,Groarke et al., J. Biol. Chem. 274(33):23263 69 (1999)).

Another technology that can be used to evaluate OR-protein interactionsin living cells involves bioluminescence resonance energy transfer(BRET). A detailed discussion regarding BRET can be found in Kroeger etal., J. Biol. Chem., 276(16):12736 43 (2001).

Other assays can involve determining the activity of receptors which,when activated by ligand binding, result in a change in the level ofintracellular cyclic nucleotides, e.g., cAMP, by activating orinhibiting downstream effectors such as adenylate cyclase. Changes inintracellular cAMP can be measured using immunoassays. The methoddescribed in Offermanns & Simon, J. Biol. Chem. 270:15175 15180 (1995)may be used to determine the level of cAMP. Also, the method describedin Felley-Bosco et al., Am. J. Resp. Cell and Mol. Biol. 11:159 164(1994) may be used to determine the level of cGMP. Further, an assay kitfor measuring cAMP a is described in U.S. Pat. No. 4,115,538, hereinincorporated by reference.

Transcription levels can be measured to assess the effects of a testcompound on ligand-induced signal transduction. A host cell containingthe protein of interest is contacted with a test compound in thepresence of the natural ligand for a sufficient time to effect anyinteractions, and then the level of gene expression is measured. Theamount of time to effect such interactions may be empiricallydetermined, such as by running a time course and measuring the level oftranscription as a function of time. The amount of transcription may bemeasured by using any method known to those of skill in the art to besuitable. For example, mRNA expression of the protein of interest may bedetected using northern blots or their polypeptide products may beidentified using immunoassays. Alternatively, transcription based assaysusing reporter genes may be used as described in U.S. Pat. No.5,436,128, herein incorporated by reference. The reporter genes can be,e.g., chloramphenicol acetyltransferase, firefly luciferase, bacterialluciferase, β-galactosidase and alkaline phosphatase. Furthermore, theprotein of interest can be used as an indirect reporter via attachmentto a second reporter such as green fluorescent protein (see, e.g.,Mistili & Spector, Nature Biotechnology 15:961 964 (1997)).

The amount of transcription is then compared to the amount oftranscription in either the same cell in the absence of the testcompound, or it may be compared with the amount of transcription in asubstantially identical cell that lacks the protein of interest. Asubstantially identical cell may be derived from the same cells fromwhich the recombinant cell was prepared but which had not been modifiedby introduction of heterologous DNA. Any difference in the amount oftranscription indicates that the test compound has in some manneraltered the activity of the protein of interest.

Pharmaceutical Compositions/Formulations

Pharmaceutical compositions can be formulated by standard techniquesusing one or more physiologically acceptable carriers or excipients. Theformulations may contain a buffer and/or a preservative. The compoundsand their physiologically acceptable salts and solvates can beformulated for administration by any suitable route, including viainhalation, topically, nasally, orally, parenterally (e.g.,intravenously, intraperitoneally, intravesically or intrathecally) orrectally in a vehicle comprising one or more pharmaceutically acceptablecarriers, the proportion of which is determined by the solubility andchemical nature of the compound, chosen route of administration andstandard biological practice.

Pharmaceutical compositions can include effective amounts of one or morecompound(s) described herein together with, for example,pharmaceutically acceptable diluents, preservatives, solubilizers,emulsifiers, adjuvants and/or other carriers. Such compositions mayinclude diluents of various buffer content (e.g., TRIS or other amines,carbonates, phosphates, amino acids, for example, glycinamidehydrochloride (especially in the physiological pH range),N-glycylglycine, sodium or potassium phosphate (dibasic, tribasic), etc.or TRIS-HCl or acetate), pH and ionic strength; additives such asdetergents and solubilizing agents (e.g., surfactants such as Pluronics,Tween 20, Tween 80 (Polysorbate 80), Cremophor, polyols such aspolyethylene glycol, propylene glycol, etc.), anti-oxidants (e.g.,ascorbic acid, sodium metabisulfite), preservatives (e.g., Thimersol,benzyl alcohol, parabens, etc.) and bulking substances (e.g., sugarssuch as sucrose, lactose, mannitol, polymers such aspolyvinylpyrrolidones or dextran, etc.); and/or incorporation of thematerial into particulate preparations of polymeric compounds such aspolylactic acid, polyglycolic acid, etc. or into liposomes. Hyaluronicacid may also be used. Such compositions can be employed to influencethe physical state, stability, rate of in vivo release, and rate of invivo clearance of a compound described herein. See, e.g., Remington'sPharmaceutical Sciences, 18th Ed. (1990, Mack Publishing Co., Easton,Pa. 18042) pages 1435-1712 which are herein incorporated by reference.The compositions can, for example, be prepared in liquid form, or can bein dried powder, such as lyophilized form. Particular methods ofadministering such compositions are described infra.

Where a buffer is to be included in the formulations described herein,the buffer can be selected from sodium acetate, sodium carbonate,citrate, glycylglycine, histidine, glycine, lysine, arginine, sodiumdihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, andtris(hydroxymethyl)-aminomethane, or mixtures thereof. The buffer canalso be glycylglycine, sodium dihydrogen phosphate, disodium hydrogenphosphate, and sodium phosphate or mixtures thereof.

Where a pharmaceutically acceptable preservative is to be included in aformulation of one of the compounds described herein, the preservativecan be selected from phenol, m-cresol, methyl p-hydroxybenzoate, propylp-hydroxybenzoate, 2-phenoxyethanol, butyl p-hydroxybenzoate,2-phenylethanol, benzyl alcohol, chlorobutanol, and thiomerosal, ormixtures thereof. The preservative can also be phenol or m-cresol.

The preservative is present in a concentration from about 0.1 mg/ml toabout 50 mg/ml, in a concentration from about 0.1 mg/ml to about 25mg/ml, or in a concentration from about 0.1 mg/ml to about 10 mg/ml.

The use of a preservative in pharmaceutical compositions is well-knownto the skilled person. For convenience reference is made to Remington:The Science and Practice of Pharmacy, 19th edition, 1995.

The formulation may further comprise a chelating agent where thechelating agent may be selected from salts of ethlenediaminetetraaceticacid (EDTA), citric acid, and aspartic acid, and mixtures thereof.

The chelating agent can be present in a concentration from 0.1 mg/ml to5 mg/ml, from 0.1 mg/ml to 2 mg/ml or from 2 mg/ml to 5 mg/ml.

The use of a chelating agent in pharmaceutical compositions iswell-known to the skilled person. For convenience reference is made toRemington: The Science and Practice of Pharmacy, 19th edition, 1995.

The formulation of the compounds described herein may further comprise astabilizer selected from high molecular weight polymers and lowmolecular compounds where such stabilizers include, but are not limitedto, polyethylene glycol (e.g. PEG 3350), polyvinylalcohol (PVA),polyvinylpyrrolidone, carboxymethylcellulose, different salts (e.g.sodium chloride), L-glycine, L-histidine, imidazole, arginine, lysine,isoleucine, aspartic acid, tryptophan, and threonine or any mixturethereof. The stabilizer can also be L-histidine, imidazole or arginine.

The high molecular weight polymer can be present in a concentration from0.1 mg/ml to 50 mg/m, from 0.1 mg/ml to 5 mg/ml, from 5 mg/ml to 10mg/ml, from 10 mg/ml to 20 mg/ml, from 20 mg/ml to 30 mg/ml or from 30mg/ml to 50 mg/ml.

The low molecular weight compound can be present in a concentration from0.1 mg/ml to 50 mg/ml, from 0.1 mg/ml to 5 mg/ml, from 5 mg/ml to 10mg/ml, from 10 mg/ml to 20 mg/ml, from 20 mg/ml to 30 mg/ml or from 30mg/ml to 50 mg/ml.

The use of a stabilizer in pharmaceutical compositions is well-known tothe skilled person. For convenience reference is made to Remington: TheScience and Practice of Pharmacy, 19th edition, 1995.

The formulation of the compounds described herein may further include asurfactant. 1N some embodiments, the surfactant may be selected from adetergent, ethoxylated castor oil, polyglycolyzed glycerides, acetylatedmonoglycerides, sorbitan fatty acid esters, poloxamers, such as 188 and407, polyoxyethylene sorbitan fatty acid esters, polyoxyethylenederivatives such as alkylated and alkoxylated derivatives (tweens, e.g.Tween-20, or Tween-80), monoglycerides or ethoxylated derivativesthereof, diglycerides or polyoxyethylene derivatives thereof, glycerol,cholic acid or derivatives thereof, lecithins, alcohols andphospholipids, glycerophospholipids (lecithins, kephalins, phosphatidylserine), glyceroglycolipids (galactopyransoide), sphingophospholipids(sphingomyelin), and sphingoglycolipids (ceramides, gangliosides), DSS(docusate sodium, docusate calcium, docusate potassium, SDS (sodiumdodecyl sulfate or sodium lauryl sulfate), dipalmitoyl phosphatidicacid, sodium caprylate, bile acids and salts thereof and glycine ortaurine conjugates, ursodeoxycholic acid, sodium cholate, sodiumdeoxycholate, sodium taurocholate, sodium glycocholate,N-Hexadecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate, anionic(alkyl-aryl-sulphonates) monovalent surfactants, palmitoyllysophosphatidyl-L-serine, lysophospholipids (e.g.1-acyl-sn-glycero-3-phosphate esters of ethanolamine, choline, serine orthreonine), alkyl, alkoxyl (alkyl ester), alkoxy (alkylether)-derivatives of lysophosphatidyl and phosphatidylcholines, e.g.lauroyl and myristoyl derivatives of lysophosphatidylcholine,dipalmitoylphosphatidylcholine, and modifications of the polar headgroup, that is cholines, ethanolamines, phosphatidic acid, serines,threonines, glycerol, inositol, and the positively charged DODAC, DOTMA,DCP, BISHOP, lysophosphatidylserine and lysophosphatidylthreonine,zwitterionic surfactants (e.g.N-alkyl-N,N-dimethylammonio-1-propanesulfonates,3-cholamido-1-propyldimethylammonio-1-propanesulfonate,dodecylphosphocholine, myristoyl lysophosphatidylcholine, hen egglysolecithin), cationic surfactants (quarternary ammonium bases) (e.g.cetyl-trimethylammonium bromide, cetylpyridinium chloride), non-ionicsurfactants, polyethyleneoxide/polypropyleneoxide block copolymers(Pluronics/Tetronics, Triton X-100, Dodecyl β-D-glucopyranoside) orpolymeric surfactants (Tween-40, Tween-80, Brij-35), fusidic acidderivatives—(e.g. sodium tauro-dihydrofusidate etc.), long-chain fattyacids and salts thereof C6-C12 (e.g. oleic acid and caprylic acid),acylcarnitines and derivatives, N_(α)-acylated derivatives of lysine,arginine or histidine, or side-chain acylated derivatives of lysine orarginine, N_(α)-acylated derivatives of dipeptides comprising anycombination of lysine, arginine or histidine and a neutral or acidicamino acid, N_(α)-acylated derivative of a tripeptide comprising anycombination of a neutral amino acid and two charged amino acids, or thesurfactant may be selected from the group of imidazoline derivatives, ormixtures thereof.

The use of a surfactant in pharmaceutical compositions is well-known tothe skilled person. For convenience reference is made to Remington: TheScience and Practice of Pharmacy, 19th edition, 1995.

Pharmaceutically acceptable sweeteners can be part of the formulation ofthe compounds described herein. Pharmaceutically acceptable sweetenersinclude at least one intense sweetener such as saccharin, sodium orcalcium saccharin, aspartame, acesulfame potassium, sodium cyclamate,alitame, a dihydrochalcone sweetener, monellin, stevioside or sucralose(4,1′,6′-trichloro-4,1′,6′-trideoxygalactosucrose), saccharin, sodium orcalcium saccharin, and optionally a bulk sweetener such as sorbitol,mannitol, fructose, sucrose, maltose, isomalt, glucose, hydrogenatedglucose syrup, xylitol, caramel, and honey.

Intense sweeteners are conveniently employed in low concentrations. Forexample, in the case of sodium saccharin, the concentration may rangefrom 0.04% to 0.1% (w/v) based on the total volume of the finalformulation, or is about 0.06% in the low-dosage formulations and about0.08% in the high-dosage ones. The bulk sweetener can effectively beused in larger quantities ranging from about 10% to about 35%, or fromabout 10% to 15% (w/v).

The formulations of the compounds described herein may be prepared byconventional techniques, e.g. as described in Remington's PharmaceuticalSciences, 1985 or in Remington: The Science and Practice of Pharmacy,19th edition, 1995, where such conventional techniques of thepharmaceutical industry involve dissolving and mixing the ingredients asappropriate to give the desired end product.

The phrase “pharmaceutically acceptable” or “therapeutically acceptable”refers to molecular entities and compositions that are physiologicallytolerable and preferably do not typically produce an allergic or similaruntoward reaction, such as gastric upset, dizziness and the like, whenadministered to a human. As used herein, the term “pharmaceuticallyacceptable” means approved by a regulatory agency of the Federal or aState government or listed in the U.S. Pharmacopeia or other generallyrecognized pharmacopeia (e.g., Remington's Pharmaceutical Sciences, MackPublishing Co. (A. R. Gennaro edit. 1985)) for use in animals, and moreparticularly in humans.

Administration of the compounds described herein may be carried outusing any method known in the art. For example, administration may betransdermal, parenteral, intravenous, intra-arterial, subcutaneous,intramuscular, intracranial, intraorbital, ophthalmic, intraventricular,intracapsular, intraspinal, intracisternal, intraperitoneal,intracerebroventricular, intrathecal, intranasal, aerosol, bysuppositories, or oral administration. A pharmaceutical composition ofthe compounds described herein can be for administration for injection,or for oral, pulmonary, nasal, transdermal, ocular administration.

For oral administration, the pharmaceutical composition of the compoundsdescribed herein can be formulated in unit dosage forms such as capsulesor tablets. The tablets or capsules may be prepared by conventionalmeans with pharmaceutically acceptable excipients, including bindingagents, for example, pregelatinised maize starch, polyvinylpyrrolidone,or hydroxypropyl methylcellulose; fillers, for example, lactose,microcrystalline cellulose, or calcium hydrogen phosphate; lubricants,for example, magnesium stearate, talc, or silica; disintegrants, forexample, potato starch or sodium starch glycolate; or wetting agents,for example, sodium lauryl sulphate. Tablets can be coated by methodswell known in the art. Liquid preparations for oral administration cantake the form of, for example, solutions, syrups, or suspensions, orthey can be presented as a dry product for constitution with water orother suitable vehicle before use. Such liquid preparations can beprepared by conventional means with pharmaceutically acceptableadditives, for example, suspending agents, for example, sorbitol syrup,cellulose derivatives, or hydrogenated edible fats; emulsifying agents,for example, lecithin or acacia; non-aqueous vehicles, for example,almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils;and preservatives, for example, methyl or propyl-p-hydroxybenzoates orsorbic acid. The preparation's can also contain buffer salts, flavoring,coloring, and/or sweetening agents as appropriate. If desired,preparations for oral administration can be suitably formulated to givecontrolled release of the active compound.

For topical administration, the pharmaceutical composition of thecompounds described herein can be formulated in a pharmaceuticallyacceptable vehicle containing 0.1 to 10 percent, or 0.5 to 5 percent, ofthe active compound(s). Such formulations can be in the form of a cream,lotion, sublingual tablet, aerosols and/or emulsions and can be includedin a transdermal or buccal patch of the matrix or reservoir type as areconventional in the art for this purpose.

For parenteral administration, the compounds described herein areadministered by either intravenous, subcutaneous, or intramuscularinjection, in compositions with pharmaceutically acceptable vehicles orcarriers. The compounds can be formulated for parenteral administrationby injection, for example, by bolus injection or continuous infusion.Formulations for injection can be presented in unit dosage form, forexample, in ampoules or in multi-dose containers, with an addedpreservative. The compositions can take such forms as suspensions,solutions, or emulsions in oily or aqueous vehicles, and can containformulatory agents, for example, suspending, stabilizing, and/ordispersing agents. Alternatively, the active ingredient can be in powderform for constitution with a suitable vehicle, for example, sterilepyrogen-free water, before use.

For administration by injection, the compound(s) can be used in solutionin a sterile aqueous vehicle which may also contain other solutes suchas buffers or preservatives as well as sufficient quantities ofpharmaceutically acceptable salts or of glucose to make the solutionisotonic. The pharmaceutical compositions of the compounds describedherein may be formulated with a pharmaceutically acceptable carrier toprovide sterile solutions or suspensions for injectable administration.Injectables can be prepared in conventional forms, either as liquidsolutions or suspensions, solid forms suitable for solution orsuspensions in liquid prior to injection or as emulsions. Suitableexcipients are, for example, water, saline, dextrose, mannitol, lactose,lecithin, albumin, sodium glutamate, cysteine hydrochloride, or thelike. In addition, if desired, the injectable pharmaceuticalcompositions may contain minor amounts of nontoxic auxiliary substances,such as wetting agents, pH buffering agents, and the like. If desired,absorption enhancing preparations (e.g., liposomes) may be utilized.Suitable pharmaceutical carriers are described in “Remington'spharmaceutical Sciences” by E. W. Martin.

For administration by inhalation, the compounds may be convenientlydelivered in the form of an aerosol spray presentation from pressurizedpacks or a nebulizer, with the use of a suitable propellant, forexample, dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In thecase of a pressurized aerosol, the dosage unit can be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof, for example, gelatin for use in an inhaler or insufflator can beformulated containing a powder mix of the compound and a suitable powderbase, for example, lactose or starch. For intranasal administration thecompounds described herein may be used, for example, as a liquid spray,as a powder or in the form of drops.

The compounds can also be formulated in rectal compositions, forexample, suppositories or retention enemas, for example, containingconventional suppository bases, for example, cocoa butter or otherglycerides.

Furthermore, the compounds can be formulated as a depot preparation.Such long-acting formulations can be administered by implantation (forexample, subcutaneously or intramuscularly) or by intramuscularinjection. Thus, for example, the compounds can be formulated withsuitable polymeric or hydrophobic materials (for example as an emulsionin an acceptable oil) or ion exchange resins, or as sparingly solublederivatives, for example, as a sparingly soluble salt.

The compositions can, if desired, be presented in a pack or dispenserdevice that can contain one or more unit dosage forms containing theactive ingredient. The pack can, for example, comprise metal or plasticfoil, for example, a blister pack. The pack or dispenser device can beaccompanied by instructions for administration.

The compounds described herein also include derivatives referred to asprodrugs, which can be prepared by modifying functional groups presentin the compounds in such a way that the modifications are cleaved,either in routine manipulation or in vivo, to the parent compounds.Examples of prodrugs include compounds of the invention as describedherein that contain one or more molecular moieties appended to ahydroxyl, amino, sulfhydryl, or carboxyl group of the compound, and thatwhen administered to a patient, cleaves in vivo to form the freehydroxyl, amino, sulfhydryl, or carboxyl group, respectively. Examplesof prodrugs include, but are not limited to, acetate, formate andbenzoate derivatives of alcohol and amine functional groups in thecompounds of the invention. Preparation and use of prodrugs is discussedin T. Higuchi et al., “Pro-drugs as Novel Delivery Systems,” Vol. 14 ofthe A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated herein by referencein their entireties.

Dosages

The compounds described herein may be administered to a patient attherapeutically effective doses to prevent, treat, or control one ormore diseases and disorders mediated, in whole or in part, by anOR-ligand interaction. Pharmaceutical compositions comprising one ormore of compounds described herein may be administered to a patient inan amount sufficient to elicit an effective protective or therapeuticresponse in the patient. An amount adequate to accomplish this isdefined as “therapeutically effective dose.” The dose will be determinedby the efficacy of the particular compound employed and the condition ofthe subject, as well as the body weight or surface area of the area tobe treated. The size of the dose also will be determined by theexistence, nature, and extent of any adverse effects that accompany theadministration of a particular compound or vector in a particularsubject.

Toxicity and therapeutic efficacy of such compounds can be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, for example, by determining the LD50 (the dose lethal to 50% ofthe population) and the ED50 (the dose therapeutically effective in 50%of the population). The dose ratio between toxic and therapeutic effectsis the therapeutic index and can be expressed as the ratio, LD50/ED50.In some embodiments, compounds that exhibit large therapeutic indicesare used. While compounds that exhibit toxic side effects can be used,care should be taken to design a delivery system that targets suchcompounds to the site of affected tissue to minimize potential damage tonormal cells and, thereby, reduce side effects.

The data obtained from cell culture assays and animal studies can beused to formulate a dosage range for use in humans. In some embodiments,the dosage of such compounds lies within a range of circulatingconcentrations that include the ED50 with little or no toxicity. Thedosage can vary within this range depending upon the dosage formemployed and the route of administration. For any compound describedherein, the therapeutically effective dose can be estimated initiallyfrom cell culture assays. A dose can be formulated in animal models toachieve a circulating plasma concentration range that includes the IC50(the concentration of the test compound that achieves a half-maximalinhibition of symptoms) as determined in cell culture. Such informationcan be used to more accurately determine useful doses in humans. Levelsin plasma can be measured, for example, by high performance liquidchromatography (HPLC). In general, the dose equivalent of a modulator isfrom about 1 ng/kg to 10 mg/kg for a typical subject.

The amount and frequency of administration of the compounds describedherein and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. An ordinarily skilledphysician or veterinarian can readily determine and prescribe theeffective amount of the drug required to prevent, counter or arrest theprogress of the condition. In general it is contemplated that aneffective amount would be from 0.001 mg/kg to 10 mg/kg body weight, andin particular from 0.01 mg/kg to 1 mg/kg body weight. It may beappropriate to administer the required dose as two, three, four or moresub-doses at appropriate intervals throughout the day. Said sub-dosesmay be formulated as unit dosage forms, for example, containing 0.01 to500 mg, and in particular 0.1 mg to 200 mg of active ingredient per unitdosage form.

In some embodiments, the pharmaceutical preparation is in a unit dosageform. In such form, the preparation is subdivided into suitably sizedunit doses containing appropriate quantities of the active component,e.g., an effective amount to achieve the desired purpose. The quantityof active compound in a unit dose of preparation may be varied oradjusted from about 0.01 mg to about 1000 mg, from about 0.01 mg toabout 750 mg, from about 0.01 mg to about 500 mg, or from about 0.01 mgto about 250 mg, according to the particular application. The actualdosage employed may be varied depending upon the requirements of thepatient and the severity of the condition being treated. Determinationof the proper dosage regimen for a particular situation is within theskill of the art. For convenience, the total dosage may be divided andadministered in portions during the day as required.

In some embodiments, one or more compounds described herein areadministered with another compound. The administration may besequentially or concurrently. The combination may be in the same dosageform or administered as separate doses. In some embodiments, the anothercompound is another analgesic or pain reliever. In some embodiments, theanother compound is a non-opioid analgesic. Examples of usefulnon-opioid analgesics include, but, are not limited to, non-steroidalanti-inflammatory agents, such as aspirin, ibuprofen, diclofenac,naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen,indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen,trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen,bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac,zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid,meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid,diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, andpharmaceutically acceptable salts thereof, and mixtures thereof. Othersuitable non-opioid analgesics include the following, non-limiting,chemical classes of analgesic, antipyretic, nonsteroidalanti-inflammatory drugs: salicylic acid derivatives, including aspirin,sodium salicylate, choline magnesium trisalicylate, salsalate,diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin;para-aminophenol derivatives including acetaminophen and phenacetin;indole and indene acetic acids, including indomethacin, sulindac, andetodolac; heteroaryl acetic acids, including tolmetin, diclofenac, andketorolac; anthranilic acids (fenamates), including mefenamic acid andmeclofenamic acid; enolic acids, including oxicams (piroxicam,tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone);and alkanones, including nabumetone. For a more detailed description ofthe NSAIDs, see Paul A. Inset, Analgesic-Antipyretic andAnti-inflammatory Agents and Drugs Employed in the Treatment of Gout, inGoodman & Gilman's The Pharmacological Basis of Therapeutics 617-57(Perry B. Molinhoff and Raymond W. Ruddon eds., 9.sup.th ed 1996); andGlen R. Hanson, Analgesic, Antipyretic and Anti-Inflammatory Drugs inRemington: The Science and Practice of Pharmacy Vol II 1196-1221 (A. R.Gennaro ed. 19.sup.th ed. 1995), which are hereby incorporated byreference in their entireties.

The compounds described herein can also be administered Cox-IIinhibitors. Examples of useful Cox-II inhibitors and 5-lipoxygenaseinhibitors, as well as combinations thereof, are described in U.S. Pat.No. 6,136,839, which is hereby incorporated by reference in itsentirety. Examples of Cox-II inhibitors include, but are not limited to,rofecoxib and celecoxib.

The compounds described herein can also be administered withantimigraine agents. Examples of useful antimigraine agents include, butare not limited to, alpiropride, bromocriptine, dihydroergotamine,dolasetron, ergocornine, ergocorninine, ergocryptine, ergonovine, ergot,ergotamine, flumedroxone acetate, fonazine, ketanserin, lisuride,lomerizine, methylergonovine, methysergide, metoprolol, naratriptan,oxetorone, pizotyline, propranolol, risperidone, rizatriptan,sumatriptan, timolol, trazodone, zolmitriptan, and mixtures thereof.

The compounds described herein can also be administered withanti-constipation agents. Examples of anti-constipation agents include,but are not limited to, laxatives or stool softners. Examples ofanti-constipation agents include, but are not limited to, be docusate,poloxamer 188, psyllium, methylcellulose, carboxymethyl cellulose,polycarbophil, bisacodyl, castor oil, magnesium citrate, magnesiumhydroxide, magnesium sulfate, dibasic sodium phosphate, monobasic sodiumphosphate, sodium biphosphate or any combination thereof.

Medical Use

The compositions described herein may be useful for treating pain orpain associated disorders. The compositions described herein may beuseful for treating immune dysfunction, inflammation, esophageal reflux,neurological and psychiatric conditions, urological and reproductiveconditions, medicaments for drug and alcohol abuse, agents for treatinggastritis and diarrhea, cardiovascular agents and agents for thetreatment of respiratory diseases and cough.

In some embodiments, methods of treating pain are provided. In someembodiments, one or more compound described herein are administered to asubject to treat the pain. In some embodiments, the pain can bepost-operative pain. In some embodiments, the pain is caused by cancer.In some embodiments, the pain is neuropathic pain. In some embodiments,the pain is caused by trauma, such as but not limited to, blunt forcetrauma. In some embodiments, the pain is caused by inflammation.

In some embodiments, the one or more compounds described herein can beadministered by any suitable route, including, but not limited to, viainhalation, topically, nasally, orally, parenterally (e.g.,intravenously, intraperitoneally, intravesically or intrathecally) orrectally in a vehicle comprising one or more pharmaceutically acceptablecarriers, the proportion of which is determined by the solubility andchemical nature of the compound, chosen route of administration andstandard practice.

DEFINITIONS

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art. Although methods and materials similar or equivalent to thosedescribed herein can be used in the practice or testing of thecompositions and compounds described herein, suitable methods andmaterials are described below. All publications, patent applications,patents, and other references mentioned herein are incorporated byreference in their entirety. In the case of conflict, the presentspecification, including definitions, will control. In addition, thematerials, methods, and examples are illustrative only not intended tobe limiting. Other features and advantages of the compositions andcompounds described herein will be apparent from the following detaileddescription and claims.

The general chemical terms used throughout have their usual meanings.For example, the term alkyl refers to a branched or unbranched saturatedhydrocarbon group. The term “n-alkyl” refers to an unbranched alkylgroup. The term “C_(x)-C_(y) alkyl” refers to an alkyl group having fromx to y carbon atoms, inclusively, in the branched or unbranchedhydrocarbon group. By way of illustration, but without limitation, theterm “C₁-C₄ alkyl” refers to a straight chain or branched hydrocarbonmoiety having from 1 to 4 carbon atoms, including methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Theterm “C₁-C₄ n-alkyl” refers to straight chain hydrocarbon moietieshaving from 1 to 4 carbon atoms including methyl, ethyl, n-propyl, andn-butyl. C_(x)-C_(y) x can be from 1 to 10 and y is from 2 to 20. Theterm “C₃-C₆ cycloalkyl” refers to cyclopropyl, cyclobutyl, cyclopentyl,and cyclohexyl. The term “C₃-C₇ cycloalkyl” also includes cycloheptyl.Cycloalkylalkyl refers to cycloalkyl moieties linked through an alkyllinker chain, as for example, but without limitation, cyclopropylmethyl,cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclobutylmethyl,cyclobutylethyl, cyclobutylpropyl, cyclopentylmethyl, cyclopentylethyl,cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl, andcyclohexylpropyl. Each alkyl, cycloalkyl, and cycloalkylalkyl group maybe optionally substituted, such as, but not limited to, as specifiedherein. In some embodiments, the alkyl is a C₁-C₃, C₁-C₄, C₁-C₆, C₄-C₆,or C₁-C₁₀ alkyl.

The terms “alkoxy”, “phenyloxy”, “benzoxy” and “pyrimidinyloxy” refer toan alkyl group, phenyl group, benzyl group, or pyrimidinyl group,respectively, that is bonded through an oxygen atom. Each of thesegroups may be optionally substituted.

The terms “alkylthio”, “phenylthio”, and “benzylthio” refer to an alkylgroup, phenyl group, or benzyl group, respectively, that is bondedthrough a sulfur atom. Each of these groups may be optionallysubstituted.

The term “C₁-C₄ acyl” refers to a formyl group or a C₁-C₃ alkyl groupbonded through a carbonyl moiety. The term “C₁-C₄ alkoxycarbonyl” refersto a C₁-C₄ alkoxy group bonded through a carbonyl moiety.

The term “halo” refers to fluoro, chloro, bromo, or iodo. In someembodiments, the halo groups are fluoro, chloro, and bromo. In someembodiments, the halo groups are fluoro and chloro.

As used herein, “carbocycle” or “carbocyclic ring” is intended to mean,unless otherwise specified, any stable 3, 4, 5, 6, 7, 8, 9, 10, 11, or12-membered monocyclic, bicyclic or tricyclic ring, any of which can besaturated, unsaturated (including partially and fully unsaturated), oraromatic. Examples of such carbocycles include, but are not limited to,cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl,cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane,fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.As shown above, bridged rings are also included in the definition ofcarbocycle (e.g., [2.2.2]bicyclooctane). A bridged ring occurs when oneor more carbon atoms link two non-adjacent carbon atoms. In someembodiments, the bridges are one or two carbon atoms. It is noted that abridge always converts a monocyclic ring into a tricyclic ring. When aring is bridged, the substituents recited for the ring can also bepresent on the bridge. Fused (e.g., naphthyl and tetrahydronaphthyl) andspiro rings are also included.

The term “heterocycle” is taken to mean a saturated or unsaturated 5- or6-membered ring containing from 1 to 3 heteroatoms selected fromnitrogen, oxygen and sulfur, said ring optionally being benzofused.Exemplary heterocycles include furanyl, thiophenyl (thienyl), pyrrolyl,pyrrolidinyl, pyridinyl, N-methylpyrrolyl, oxazolyl, isoxazolyl,pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl,thiazolidinyl, N-acetylthiazolidinyl, pyrimidinyl, pyrazinyl,pyridazinyl, and the like. Benzofused heterocyclic rings includeisoquinolinyl, benzoxazolyl, benzodioxolyl, benzothiazolyl, quinolinyl,benzofuranyl, benzothiophenyl, indolyl, and the like, all of which maybe optionally substituted, which also of course includes optionallysubstituted on the benzo ring when the heterocycle is benzofused.

The term “cycle” group is taken to mean a carbocylic ring, a carbocycleor a heterocarbocyle.

As used herein, the phrase a “cycle of the formula” refers to a ringthat can be formed with the variable referred to. For example, in thestructure

wherein A can be a cycle of the formula C(CH₂)_(n), where n=2-5, itmeans that A is a carbon and forms a ring with itself with 2-5 CH₂groups, which could also be represented structurally as

The variable “A” is not limited to carbon and can be another atom, suchas, but not limited to, a heteroatom, but the context in which thevariable is used will indicate the type of atom “A” could be. This isjust a non-limiting example. Additionally, the ring that is formed with“A” can also be substituted. Exemplary substituents are describedherein.

In some embodiments, heterocycles include, but are not limited to,pyridinyl, indolyl, furanyl, benzofuranyl, thiophenyl, benzodioxolyl,and thiazolidinyl, all of which may be optionally substituted.

As used herein, the term “aromatic heterocycle” or “heteroaryl” isintended to mean a stable 5, 6, 7, 8, 9, 10, 11, or 12-memberedmonocyclic or bicyclic aromatic ring which consists of carbon atoms andone or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6heteroatoms, independently selected from nitrogen, oxygen, and sulfur.In the case of bicyclic heterocyclic aromatic rings, only one of the tworings needs to be aromatic (e.g., 2,3-dihydroindole), though both can be(e.g., quinoline). The second ring can also be fused or bridged asdefined above for heterocycles. The nitrogen atom can be substituted orunsubstituted (i.e., N or NR wherein R is H or another substituent, asdefined). The nitrogen and sulfur heteroatoms can optionally be oxidized(i.e., N→O and S(O)_(p), wherein p=1 or 2). In certain compounds, thetotal number of S and O atoms in the aromatic heterocycle is not morethan 1.

Examples of heterocycles include, but are not limited to, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

Substituted alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, or alkylthio,means an alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, or alkylthio group,respectively, substituted one or more times independently with asubstituent selected from the group consisting of halo, hydroxy, andC₁-C₃ alkoxy. By way of illustration, but without limitation, examplesinclude trifluoromethyl, pentafluoroethyl, 5-fluoro-2-bromopentyl,3-hydroxypropyloxy, 4-hydroxycyclohexyloxy, 2-bromoethylthio,3-ethoxypropyloxy, 3-ethoxy-4-chlorocyclohexyl, and the like. In someembodiments, substitutions include substitution 1-5 times with halo,each independently selected, or substituted 1-3 times with halo and 1-2times independently with a group selected from hydroxy and C₁-C₃ alkoxy,or substituted 1-3 times independently with a group selected fromhydroxy and C₁-C₃ alkoxy, provided that no more than one hydroxy and/oralkoxy substituent may be attached through the same carbon.

The terms “substituted phenyl” and “substituted heterocycle” are takento mean that the cyclic moiety in either case is substituted. They canbe substituted independently with one or more substituents. They can besubstituted independently with 1, 2, 3, 4, 5, 1-3, 1-4, or 1-5substituents. The substitution can be, independently, halo, alkyl, suchas, but not limited to, C₁-C₄ alkyl, alkoxy, such as but not limited to,C₁-C₄ alkoxy, and alkylthio, such as but not limited to, C₁-C₄alkylthio, wherein each alkyl, alkoxy and alkylthio substituent can befurther substituted independently with C₁-C₂ alkoxy or with one to fivehalo groups; or substituted with one substituent selected from the groupconsisting of phenyloxy, benzyloxy, phenylthio, benzylthio, andpyrimidinyloxy, wherein the phenyloxy, benzyloxy, phenylthio,benzylthio, and pyrimidinyloxy moiety can be further substituted withone to two substituents selected from the group consisting of halo,C₁-C₂ alkyl, and C₁-C₂ alkoxy; or substituted with one substituentselected from the group consisting of C₁-C₄ acyl and C₁-C₄alkoxycarbonyl, and further substituted with zero to one substituentselected from the group consisting of halo, C₁-C₄ alkyl, C₁-C₄ alkoxy,and C₁-C₄ alkylthio. When a substituent is halo, in some embodiments,the halo groups are fluoro, chloro, and bromo. The halo can also beiodo.

DMF means N,N-dimethylformamide.

As used herein, the phrase “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

By “pharmaceutical formulation” it is further meant that the carrier,solvent, excipients and salt must be compatible with the activeingredient of the formulation (e.g. a compound described herein). It isunderstood by those of ordinary skill in this art that the terms“pharmaceutical formulation” and “pharmaceutical composition” aregenerally interchangeable, and they are so used for the purposes of thisapplication.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary, ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include, but are not limited to, thosederived from inorganic and organic acids selected from 2-acetoxybenzoic,2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic,bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic,glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic,hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic,lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic,phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic,succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic. The present disclosure includes pharmaceutically acceptablesalts of any compound(s) described herein.

Pharmaceutically acceptable salts can be synthesized from the parentcompound that contains a basic or acidic moiety by conventional chemicalmethods. Generally, such salts can be prepared by reacting the free acidor base forms of these compounds with a stoichiometric amount of theappropriate base or acid in water or in an organic solvent, or in amixture of the two; generally, non-aqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile, and the like. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 18thed., Mack Publishing Company, Easton, Pa., USA, p. 1445 (1990).

Since prodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.)the compounds described herein can be delivered in prodrug form and canbe administered in this form for the treatment of disease. “Prodrugs”are intended to include any covalently bonded carriers that release anactive parent drug of described herein in vivo when such prodrug isadministered to a mammalian subject. Prodrugs are prepared by modifyingfunctional groups present in the compound in such a way that themodifications are cleaved, either in routine manipulation or in vivo, tothe parent compound. Prodrugs include compounds described herein whereina hydroxy, amino, or sulfhydryl group is bonded to any group that, whenthe prodrug is administered to a mammalian subject, it cleaves to form afree hydroxyl, free amino, or free sulfhydryl group, respectively.Examples of prodrugs include, but are not limited to, acetate, formate,and benzoate derivatives of alcohol and amine functional groups in thecompounds described herein.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

As used herein, “treating” or “treatment” includes any effect e.g.,lessening, reducing, modulating, or eliminating, that results in theimprovement of the condition, disease, disorder, etc. “Treating” or“treatment” of a disease state means the treatment of a disease-state ina mammal, particularly in a human, and include: (a) inhibiting anexisting disease-state, i.e., arresting its development or its clinicalsymptoms; and/or (c) relieving the disease-state, i.e., causingregression of the disease state.

As used herein, “preventing” means causing the clinical symptoms of thedisease state not to develop i.e., inhibiting the onset of disease, in asubject that may be exposed to or predisposed to the disease state, butdoes not yet experience or display symptoms of the disease state.

As used herein, “mammal” refers to human and non-human patients.

As used herein, the term “therapeutically effective amount” refers to acompound, or a combination of compounds, described herein present in oron a recipient in an amount sufficient to elicit biological activity,e.g. pain relief. In some embodiments, the combination of compounds is asynergistic combination. Synergy, as described, for example, by Chou andTalalay, Adv. Enzyme Regul. vol. 22, pp. 27-55 (1984), occurs when theeffect of the compounds when administered in combination is greater thanthe additive effect of the compounds when administered alone as a singleagent. In general, a synergistic effect is most clearly demonstrated atsub-optimal concentrations of the compounds. Synergy can be in terms oflower cytotoxicity, increased decrease in pain, or some other beneficialeffect of the combination compared with the individual components.

All percentages and ratios used herein, unless otherwise indicated, areby weight.

Throughout the description, where compositions are described as having,including, or comprising specific components, or where processes aredescribed as having, including, or comprising specific process steps, itis contemplated that compositions described herein also consistessentially of, or consist of, the recited components, and that theprocesses described herein also consist essentially of, or consist of,the recited processing steps. Further, it should be understood that theorder of steps or order for performing certain actions are immaterial solong as the process remains operable. Moreover, two or more steps oractions can be conducted simultaneously.

All enantiomers, diastereomers, and mixtures thereof, are includedwithin the scope of compounds described herein. In some embodiments, acomposition comprising the R enantiomer is free or substantially free ofthe S enantiomer. In some embodiments, a composition comprising the Senantiomer is free or substantially free of the R enantiomer. In someembodiments, a composition comprises an enantiomeric excess of at least,or about, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99% of either theR or the S enantiomer.

As used throughout this disclosure, the singular forms “a,” “an,” and“the” include plural reference unless the context clearly dictatesotherwise. Thus, for example, a reference to “a composition” includes aplurality of such compositions, as well as a single composition; and areference to “a therapeutic agent” is a reference to one or moretherapeutic and/or pharmaceutical agents and equivalents thereof knownto those skilled in the art, and so forth. Thus, for example, areference to “a host cell” includes a plurality of such host cells, anda reference to “an antibody” is a reference to one or more antibodiesand equivalents thereof known to those skilled in the art, and so forth.

The claimed compounds in this invention can be prepared from theprocedures described in the schemes below.

Schemes

The following representative schemes illustrate how compounds describedherein can be prepared. The specific solvents and reaction conditionsreferred to are also illustrative and are not intended to be limited.Compounds not described are either commercially available or are readilyprepared by one skilled in the art using available starting materials.

In some embodiments, the same scheme is applied to 1-7 and 1-8A.

In some embodiments, the same scheme is applied to 1-7 and 1-8A.

In some embodiments, 4-1 is selected from the group consisting of

Following a sequence outlined in Scheme 2 or 3, intermediate 4-4 can beconverted to the opioid receptor ligands.

Other schemes can also be used. For example, the following schemes canbe used alone or in combination with other schemes to prepare thecompounds described herein.

In some embodiments, a process for preparing a compound having thestructure of IV-1

is provided. In some embodiments, the process comprises contacting

with

under suitable conditions to form a compound having the structure of

In some embodiments, the process is performed at room temperature. Insome embodiments, the process is performed in the presence of aborohydrate salt. In some embodiments, the process is performed in thepresence of sodium borohydrate. Solvents can also be used to facilitatethe preparation. The process can be modified to yield different alkylgroups, such as, but not limited to, the scheme shown in Scheme 10.

EXAMPLES

The following examples are illustrative, but not limiting, of themethods and compositions described herein. Other suitable modificationsand adaptations of the variety of conditions and parameters normallyencountered in therapy and that are obvious to those skilled in the artare within the spirit and scope of the compounds and methods describedherein.

Example 1 Intermediate 1: methyl 2-cyano-2-(oxan-4-ylidene)acetate

A 50 ml round-bottom flask equipped with a Dean-Stark distillation setupand condenser was charged with tetrahydro-4H-pyran-4-one (4.61 ml, 50mmol), methyl cyanoacetate (5.3 ml, 60 mmol), ammonium acetate (1 g, 13mmol), acetic acid (0.57 ml, 10 mmol) and benzene (30 ml). The mixturewas refluxed until no more water collected in the Dean-Stark (2 hours),cooled, benzene (30 ml) added and the organic layer washed with water(50 ml). The aqueous layer was extracted with CH₂Cl₂ (3×50 ml). Thecombined organic phase was washed with sat. NaHCO₃ (100 ml), brine (100ml) dried (MgSO₄), filtered and concentrated. Purified by normal phaseSiO₂ chromatography (10 to 60% EtOAc/hexanes) to afford methyl2-cyano-2-(oxan-4-ylidene)acetate as a colorless oil (6.30 g, 70%, m/z:181.1 [M+H]⁺ observed).

Intermediate 2: methyl 2-cyano-2-[4-(4-fluorophenyl)oxan-4-yl]acetate

A round bottom flask was equipped with a condenser, addition funnel andrubber septum with nitrogen inlet was charged with a solution ofp-fluorophenylmagnesium bromide (2.0 M in diethyl ether, 1.99 ml, 3.97mmol) and CuI (63 mg, 0.331 mmol) in 10 ml dry diethyl ether (10 ml).Methyl 2-cyano-2-(oxan-4-ylidene)acetate (600 mg, 3.31 mmol) in diethylether (10 ml) was added drop-wise over 30 min while cooling the reactionflask in an ice bath. The mixture was then stirred for 3 h. The reactionmixture was poured into a 50 g ice/1 N HCl (25 ml) mixture. The productwas extracted with Et₂O (3×50 ml), washed with brine (50 ml), dried(NA₂SO₄) and concentrated. Purified by normal phase SiO₂ chromatography(7% to 60% EtOAc/hexanes) to give methyl2-cyano-2-[4-(4-fluorophenyl)oxan-4-yl]acetate as a white solid (730 mg,80%, m/z: 277.1 [M+Na]⁺ observed).

Intermediate 3: 2-[4-(4-fluorophenyl)oxan-4-yl]acetonitrile

To a pre-dissolved solution of KOH (441 mg, 7.87 mmol) in ethyleneglycol (20 ml) was added methyl2-cyano-2-[4-(4-fluorophenyl)oxan-4-yl]acetate (1.09 g, 3.93 mmol). Themixture was heated to 120° C. for 3 h, and then cooled. H₂O was added(50 ml), the product extracted with Et₂O (3×50 ml), washed with H₂O (50ml), dried over NA₂SO₄, filtered and concentrated. Purified by normalphase SiO₂ chromatography (5 to 40% EtOAc/hexanes) to give2-[4-(4-fluorophenyl)oxan-4-yl]acetonitrile as a colorless oil (450 mg,78%, m/z: 219.1 [M+H]⁺ observed).

Intermediate 4: 2-[4-(4-fluorophenyl)oxan-4-yl]ethan-1-amine

To a solution of 2-[4-(4-fluorophenyl)oxan-4-yl]acetonitrile (450 mg,2.05 mmol) in anhydrous ether (15 ml) at 0° C. was added dropwise LAH(1.0 M in Et₂O, 4.1 ml, 4.11 mmol). After 2 h the reaction was quenchedwith 1 ml H₂O, 0.1 ml 15% NaOH and then 1 ml H₂O. The reaction mixturewas extracted with Et₂O (3×20 ml), dried over NA₂SO₄ and concentrated togive 2-[4-(4-fluorophenyl)oxan-4-yl]ethan-1-amine as an yellow oil,which used without further purification (450 mg, 94%, m/z: 223.1 [M+H]⁺observed).

Example 2 benzyl({2-[4-(4-fluorophenyl)oxan-4-yl]ethyl})amine (Compound8)

To a solution of 2-[4-(4-fluorophenyl)oxan-4-yl]ethan-1-amine (250 mg,1.12 mmol) in anhydrous CH₂Cl₂ (5 ml) and NA₂SO₄ (159 mg, 1.12 mmol) atrt was added benzaldehyde (0.17 ml, 1.68 mmol). The reaction was stirredovernight. The reaction mixture was filtered and concentrated. Theresidue was dissolved in 5 ml MeOH at 0° C. and NaBH₄ added in oneportion (51 mg, 1.34 mmol). The reaction was stirred at 0° C. for 1 h.The solution was then quenched with H₂O (10 ml), extracted with CH₂Cl₂(3×20 ml), washed with brine (10 ml) and dried over NA₂SO₄. Purified bynormal phase SiO₂ chromatography (0 to 10% MeOH/CH₂Cl₂) to givebenzyl({2-[4-(4-fluorophenyl)oxan-4-yl]ethyl})amine as a colorless oil(200 mg, 60%, m/z: 314.2 [M+H]⁺ observed).

Intermediate 5: 2,2-dimethyl-4-(4-methylphenyl)oxan-4-ol

n-BuLi (26.3 ml, 1.6 M in hexane, 42 mmol) was added dropwise to asolution of 4-bromo-toluene (7.70 g, 45 mmol) in THF (100 ml) at −78° C.under N₂. The resulting mixture was stirred at −78° C. for 30 min and asolution of tetrahydro-2,2-dimethyl-4H-pyran-4-one (3.84 g, 30 mmol) inTHF (20 ml) was added. The resulting mixture was stirred at −78° C. foranother 20 min and quenched by adding MeOH (10 ml). The reaction wasconcentrated under vacuum and the resulting residue was diluted withEtOAc (500 ml) and washed with sat. NH₄Cl (250 ml), brine (250 ml),dried and concentrated to give 2,2-dimethyl-4-(4-methylphenyl)oxan-4-olas a white solid, which was used without further purification (5.41 g,82%).

¹H NMR (400 MHz, CDCl₃) δ 7.36-7.26 (m, 2H), 7.11 (d, J=8.0, 2H), 4.10(td, J=12.0, 2.2, 1H), 3.71 (ddd, J=11.8, 5.0, 2.1, 1H), 2.28 (s, 3H),2.11 (ddd, J=13.7, 12.2, 5.0, 1H), 1.72 (dt, J=14.2, 8.3, 2H), 1.58 (dq,J=13.8, 2.2, 1H), 1.44 (s, 3H), 1.38 (s, 1H), 1.14 (s, 3H).

Intermediate 6: 2,2-dimethyl-4-(4-methylphenyl)-4-(prop-2-en-1-yl)oxane

Allyltrimethylsilane (4.34 ml, 27.2 mmol) was added to a solution of2,2-dimethyl-4-(4-methylphenyl)oxan-4-ol (3.0 g, 13.6 mmol) in dryCH₂Cl₂ (100 ml) at 0° C., followed by BF₃—OEt₂ (3.42 ml, 27.2 mmol). Theresulting mix was stirred at 0° C. for 1 h. The reaction was quenchedwith H₂O (10 ml) and diluted with CH₂Cl₂ (10 ml), and washed with sat.NaHCO₃ (20 ml), brine (20 ml), dried and concentrated. Purified bynormal phase SiO₂ chromatography (5 to 40% EtOAc/hexanes) to give2,2-dimethyl-4-(4-methylphenyl)-4-(prop-2-en-1-yl)oxane as a colorlessoil, which was used crude (2.49 g, 75%).

Intermediate 7: 2-[2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]acetaldehyde

O₃ gas was passed through a solution of2,2-dimethyl-4-(4-methylphenyl)-4-(prop-2-en-1-yl)oxane (1.21 g, 5 mmol)in CH₂Cl₂ (50 ml) at −78° C. until the solution turned light blue (about5 min). After additional 5 minutes, the reaction mix was purged withoxygen gas for 15 min before adding triphenylphosphine (2.62 g, 10mmol). The reaction was stirred at rt for 4 h and concentrated. Purifiedby normal phase SiO₂ chromatography (10 to 60% EtOAc/hexanes) to give2-[2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]acetaldehyde as a colorlessoil (641 mg, 52%).

¹H NMR (400 MHz, CDCl₃) δ 9.42-9.27 (m, 1H), 7.26 (dd, J=9.9, 8.0, 2H),7.20 (t, J=8.7, 2H), 3.94-3.75 (m, 2H), 2.69 (dd, J=14.6, 2.5, 1H),2.51-2.38 (m, 2H), 2.35 (s, 3H), 2.26 (dd, J=13.9, 2.3, 1H), 1.84 (ddd,J=14.3, 11.0, 4.6, 1H), 1.76 (d, J=13.9, 1H), 1.23 (s, 3H), 0.73 (s,3H).

Example 3{2-[2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl}[(3-methylphenyl)methyl]amine(Compound 32)

A mixture of 2-[2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]acetaldehyde(61.6 mg, 0.25 mmol), 3-methylbenzylamine (63 μl, 0.5 mmol) and aceticacid (50 μl, 8.6 mmol) in CH₂Cl₂ (3 ml) was stirred at rt for 1 h beforeit adding sodium triacetoxyborohydride (106 mg, 0.50 mmol). Theresulting mixture was stirred at rt for 18 h. The mix was concentratedand dissolved in MeOH and purified by HPLC to give{2-[2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl}[(3-methylphenyl)methyl]amineas a white solid (35 mg, 40%, m/z: 352.3 [M+H]⁺ observed).

Intermediate 8: methyl2-cyano-2-[(9Z)-6-oxaspiro[4.5]decan-9-ylidene]acetate

A 100 ml round-bottom flask equipped with a Dean-Stark distillationsetup and condenser was charged with 6-oxaspiro[4.5]decan-9-one (6 g, 39mmol, which was prepared according to Hanschke, E. Chem. Ber. 1955, 88,1053), methyl cyanoacetate (4.1 ml, 46.7 mmol), ammonium acetate (780mg, 10.1 mmol), acetic acid (0.44 ml, 7.8 mmol) and benzene (40 ml). Themixture was refluxed until no more water collected in the Dean-Stark (2hours), cooled, benzene (30 ml) added and the organic washed with water(50 ml). The aqueous layer was extracted with CH₂Cl₂ (3×50 ml). Thecombined organic phase was washed with sat. NaHCO₃ (100 ml), brine (100ml) dried (MgSO₄), filtered and concentrated. Purified by normal phaseSiO₂ chromatography (7% to 60% EtOAc/hexanes) to give methyl2-cyano-2-[(9Z)-6-oxaspiro[4.5]decan-9-ylidene]acetate as a colorlessoil (8.93 g, 97.5%, m/z 235.1 [M+H]⁺ observed).

By the procedure for the preparation of intermediate 8 substituting2,2-diethyloxan-4-one for 6-oxaspiro[4.5]decan-9-one, methyl2-cyano-2-[(4Z)-2,2-diethyloxan-4-ylidene]acetate was prepared (m/z237.1 [M+H]⁺ observed).

By the procedure for the preparation of intermediate 8 substituting1-oxaspiro[5.5]undecan-4-one for 6-oxaspiro[4.5]decan-9-one, methyl2-cyano-2-[(4Z)-1-oxaspiro[5.5]undecan-4-ylidene]acetate was prepared(m/z 249.1 [M+H]⁺ observed).

Intermediate 9: methyl2-cyano-2-[9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl]acetate

A round bottom flask was equipped with a condenser, addition funnel andrubber septum with nitrogen inlet was charged with a solution of4-fluoromagnesium bromide (2.0 M in diethyl ether, 7.5 ml, 12.5 mmol)and CuI (200 mg, 1.0 mmol) in 35 ml dry diethyl ether. Methyl2-cyano-2-[(9Z)-6-oxaspiro[4.5]decan-9-ylidene]acetate (2.5 g, 10.5mmol) in diethyl ether (35 ml) was added drop-wise over 30 min whilecooling the reaction flask in an ice bath. The mixture was then stirredat room temperature for 1 h. The reaction mixture was poured into a 25 gice/1 N HCl (20 ml) mixture. The product was extracted with Et₂O (3×50ml), washed with brine (50 ml), dried (NA₂SO₄) and concentrated.Purified by normal phase SiO₂ chromatography (8% to 60% EtOAc/hexanes)to give methyl2-cyano-2-[9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl]acetate as acolorless oil (3.24 g, 93%, m/z 331.2 [M+H]⁺ observed).

By the procedure described in the preparation of intermediate 9substituting methyl 2-cyano-2-[(4Z)-2,2-diethyloxan-4-ylidene]acetatefor methyl 2-cyano-2-[(9Z)-6-oxaspiro[4.5]decan-9-ylidene]acetate,methyl 2-cyano-2-[2,2-diethyl-4-(4-fluorophenyl)oxan-4-yl]acetate wasprepared (m/z 333.2 [M+H]⁺ observed).

By the procedure described in the preparation of intermediate 9substituting methyl2-cyano-2-[(4Z)-1-oxaspiro[5.5]undecan-4-ylidene]acetate for methyl2-cyano-2-[(9Z)-6-oxaspiro[4.5]decan-9-ylidene]acetate, methyl2-cyano-2-[4-(4-fluorophenyl)-1-oxaspiro[5.5]undecan-4-yl]acetate wasprepared (m/z 345.2 [M+H]⁺ observed).

Intermediate 10:2-[(9R)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl]acetonitrile

To a pre-dissolved solution of KOH (1.1 g, 19.5 mmol) in ethylene glycol(50 ml) was added methyl2-cyano-2-[9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl]acetate (3.24 g,9.8 mmol). The mixture was heated to 120° C. for 3 h, then cooled. H₂Owas added (50 ml), the product extracted with Et₂O (3×50 ml), washedwith H₂O (50 ml), dried over NA₂SO₄, filtered and concentrated. (7% to60% EtOAc/hexanes) to give methyl2-cyano-2-[9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl]acetate (1.96 g,73%, m/z 273.2 [M+H]⁺ observed).

1.96 g of the enantiomers were separated by SFC on an AD-3 column using15% MeOH (0.05% DEA) as a modifier to give2-[(9S)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl]acetonitrile as acolorless oil (faster eluting enantiomer, 635 mg, 24%, m/z 274.2 [M+H]⁺observed) and2-[(9R)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl]acetonitrile as acolorless oil (slower eluting enantiomer, 703 mg, 26%, m/z 273.2 [M+H]⁺observed).

By the procedure described in the preparation of intermediate 10substituting methyl2-cyano-2-[2,2-diethyl-4-(4-fluorophenyl)oxan-4-yl]acetate for methyl2-cyano-2-[9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl]acetate,2-[2,2-diethyl-4-(4-fluorophenyl)oxan-4-yl]acetonitrile was prepared(m/z 275.2 [M+H]⁺ observed).

By the procedure described in the preparation of intermediate 10substituting methyl2-cyano-2-[4-(4-fluorophenyl)-1-oxaspiro[5.5]undecan-4-yl]acetate formethyl 2-cyano-2-[9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl]acetate,2-[4-(4-fluorophenyl)-1-oxaspiro[5.5]undecan-4-yl]acetonitrile wasprepared (m/z 287.2 [M+H]⁺ observed).

Intermediate 11:2-[(9R)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl]ethan-1-amine

To a solution of2-[(9R)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl]acetonitrile (500mg, 1.8 mmol) in anhydrous ether (30 ml) at 0° C. was added dropwise LAH(1.0 M in Et₂O, 3.7 ml, 3.7 mmol). The reaction was then warmed up toroom temperature. After 2 h the reaction was quenched with 1 ml H₂O, 0.2ml 15% NaOH and then 1 ml H₂O. The reaction mixture was extracted withEt₂O (3×30 ml), dried over NA₂SO₄ and concentrated to give2-[(9R)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl]ethan-1-amine as anyellow oil, which used without further purification (500 mg, 100%, m/z277.2 [M+H]⁺ observed).

By the procedure described in the preparation of intermediate 11substituting 2-[2,2-diethyl-4-(4-fluorophenyl)oxan-4-yl]acetonitrile for2-[(9R)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl]acetonitrile,2-[2,2-diethyl-4-(4-fluorophenyl)oxan-4-yl]ethan-1-amine was prepared(m/z 279.2 [M+H]⁺ observed).

By the procedure described in the preparation of intermediate 11substituting2-[4-(4-fluorophenyl)-1-oxaspiro[5.5]undecan-4-yl]acetonitrile for2-[(9R)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl]acetonitrile,2-[4-(4-fluorophenyl)-1-oxaspiro[5.5]undecan-4-yl]ethan-1-amine wasprepared (m/z 291.2 [M+H]⁺ observed).

Example 4benzyl({2-[(9R)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine(Compound 81)

To a solution of amine2-[(9R)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl]ethan-1-amine (100mg, 0.361 mmol) in anhydrous CH₂Cl₂ (6 ml) and NA₂SO₄ (256 mg, 1.80mmol) at rt was added benzaldehyde (0.055 ml; 0.541 mmol). The reactionwas stirred overnight. The reaction mixture was filtered andconcentrated. The residue was dissolved in 6 ml MeOH at 0° C. and NaBH₄added in one portion (16 mg, 0.433 mmol). The reaction was stirred at 0°C. for 1 h. The solution was then quenched with H₂O (20 ml), extractedwith CH₂Cl₂ (3×30 ml), washed with brine (10 ml) and dried over NA₂SO₄.The mixture was purified by HPLC to givebenzyl({2-[(9R)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amineas a white solid (121 mg, 92%, m/z 368.3 [M+H]⁺ observed).

Intermediate 12: 2,2-diethyloxan-4-ol

To a mixture of 3-butene-1-ol (19.8 ml; 233 mmol) and 3-pentenone (12.3ml; 116 mmol) was added 75% sulfuric acid (19.8; 334 mmol; prepared bydiluting 79 ml of conc. sulfuric acid to 100 ml with distilled water)drop-wise at 0° C. The reaction was allowed to warm to room temperatureand stirred overnight. Water (70 ml) was added to the mixture thenneutralized with NaOH (pellets) to pH 8 and extracted with diethyl ether(3×150 ml). The ether extract was washed with an aqueous sodiumbisulfite solution (40 ml), dried over K₂CO₃ and the ether evaporated invacuo. The residue was distilled under reduced pressure to give2,2-diethyloxan-4-ol (4.89 g, 27%, B. Pt. 65-70° C. at 1 mm Hg).

¹H NMR (400 MHz, CDCl₃) δ 4.04-3.86 (m, 1H), 3.84-3.66 (m, 1H),3.65-3.38 (m, 1H), 2.06-1.95 (m, 1H), 1.92-1.76 (m, 2H), 1.78-1.63 (m,1H), 1.63-1.50 (m, 1H), 1.51-1.31 (m, 3H), 1.28-1.10 (m, 1H), 0.92-0.68(m, 6H).

Intermediate 13: 2,2-diethyloxan-4-one

To a solution of crude 2,2-diethyloxan-4-ol (500 mg, 3.2 mmol) in CH₂Cl₂(10 ml) were added NMO (750 mg, 6.41 mmol) and 4 A molecular sieves (2g). The solution was stirred for 30 mins and then TPAP (34 mg, 0.096mmol) was added in one portion. The reaction was allowed to stir for 10h. After checking the TLC, the alcohol was gone. It was filtered througha short pad of SiO₂. The filtrate was concentrated and purified bynormal phase SiO₂ chromatography (0% to 50% EtOAc/hexanes) to give2,2-diethyloxan-4-one (365 mg, 73%).

¹H NMR (400 MHz, CDCl₃) δ 3.75-3.66 (m, 2H), 3.44-3.29 (m, 2H),2.51-2.31 (m, 4H), 1.25-1.4 (m, 4H), 0.75 (m, 6H).

Intermediate 14: 2-(bromomagnesio)pyridine

Into a flask was placed isopropylmagnesium chloride 2.0M in THF (6 mL,12 mmole), 2-bromopyridine (1.2 mL, 12 mmol) in anhydrous Et₂O (4 ml)added dropwise. The reaction mixture was stirred at rt. for 3 h. Theresulting mixture was used as is as 1M Grignard solution.

Example 5dibenzyl({2-[(9R)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine(Compound 225)

To a solution of2-[(9R)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl]acetonitrile (30mg, 0.13 mmol) in anhydrous CH₂Cl₂ (3 ml) and NA₂SO₄ (92.3 mg, 0.65mmol) at rt was added 2.3 eq benzaldehyde (0.032 ml, 0.32 mmol); Thereaction was stirred overnight. NaBH(OAc)₃ (6.6 mg, 0.31 mmol) added inone portion. The solution was then quenched with H₂O (10 ml), extractedwith CH₂Cl₂ (3×20 ml), washed with brine (10 ml) and dried over NA₂SO₄.The solvent was evaporated in vacuo and the residue was purified by HPLCto obtaindibenzyl({2-[(9R)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine(37.4 mg, 50%, m/z 458.3 [M+H]⁺ observed).

Example 6{2-[(9R)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl]ethyl}[(3-methylphenyl)methyl]amine(Compound 122)

Following an analogueous procedure described for Compound 81, Compound122 was obtained from the corresponding intermediate after a chiral HPLCseparation (The slower moving fraction on AD-3 column. The absoluteconfiguration of Ex. 122 was determined by an X-ray crystallography.

Example 7{2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl}[2-(pyridin-3-yl)ethyl]amine(Compound 75)

1.0 M DIBAL solution in toluene (3.0 ml, 3 mmol) was added drop-wise toa solution of2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetonitrile (350 mg,1.4 mmol) in 7 mL toluene at −78° C. The resulting mixture was stirredat −78° C. until completion (1.5 h). The reaction was then quenched with5 eq of MeOH (0.28 mL) and 0.1 mL water, stir while warming, 175 mgNA₂SO₄ added, stir at room temp. 2 h to give 310 mg (80%) of2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetaldehyde. LCMSm/z 250.6 (M+1) observed.

To a solution of2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetaldehyde (50 mg,0.19 mmole), 5 mL DCM and NA₂SO₄ (134 mg, 0.95 mmole) was added2-(pyridin-3-yl)ethan-1-amine (31 mg, 0.25 mmole) and the reaction wasstirred overnight. NaBH₄ (9.5 mg, 0.25 mmole) added, stir 10 minutes, 2drops MeOH added, stir 1 h, quenched with water, organics separated offand evaporated. The residue was passed through a Gilson reverse phaseHPLC to give{2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl}[2-(pyridin-3-yl)ethyl]amine,65.3 mg (71%). LCMS m/z 367.1 (M+1) observed.

Example 82-[(9R)-9-(2-{4H,5H,6H-thieno[2,3-c]pyrrol-5-yl}ethyl)-6-oxaspiro[4.5]decan-9-yl]pyridine(Compound 82)

To a stirred solution of2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethan-1-amine (0.030g, 0.115 mmol; prepared by following a sequence described for Compound81 in dried ACN (5.8 mL) was added 2,3-bis(bromomethyl)thiophene (31.1mg, 0.115 mmol) followed by addition of K₂CO₃ (79.62 mg, 0.576 mmol).After 30 min, LCMS showed that the reaction was done and the major peakhad the corresponding mass to the desired product. It was then subjectedto HPLC purification. HPLC purification method: Luna acid medium column,10-50% acetonitrile in H₂O over 15 min, followed by flashing with 100%acetonitrile, 0.1% TFA modifier was employed. The fractions containingthe desired product were pooled, basified with 2N NaOH and extractedwith DCM (3×20 mL). The combined organics were concentrated and purifiedwith flash chromatography (10 g silica gel column, eluted by 0-10% MeOHin DCM, based upon TLC measurement: DCM/MeOH (10/1) Rf=0.60) to afford 5mg of2-[(9R)-9-(2-{4H,5H,6H-thieno[2,3-c]pyrrol-5-yl}ethyl)-6-oxaspiro[4.5]decan-9-yl]pyridineas a colorless oil in 12% yield.

LCMS m/z 369 (M+1) observed.

Example 9{2-[9-(1H-pyrazol-1-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl}(thiophen-2-ylmethyl)amine(Compound 26)

An oven-dried flask equipped with a Dean-Stork apparatus and condenserwas cooled to rt under a stream of N₂ and was charged with6-oxaspiro[4.5]decan-9-one (0.50 g, 3.24 mmol),(tert-butoxy)carbohydrazide (0.42 g, 3.24 mmol) and hexane (10 mL). Theresulting solution was heated to reflux overnight.

It was cooled to rt and the solid collected by vacuum filtration. Thesolid was washed with hexane and air-dried to give(tert-butoxy)-N′-[(9Z)-6-oxaspiro[4.5]decan-9-ylidene]carbohydrazide(0.84 g, 96% yield). LCMS m/z 213 (M+1-t-butyl) observed.

An oven-dried flask was charged with(tert-butoxy)-N′-[(9Z)-6-oxaspiro[4.5]decan-9-ylidene]carbohydrazide(0.42 g, 1.56 mmol) and THF. The solution was cooled to 0° C. andallylmagnesiumchloride (2.0 M, 1.60 mL) was added dropwise. The reactionwas stirred at 0° C. for 1 h and the warmed to rt overnight. LC-MSindicated the reaction didn't go to completion. Another 2 equivalent ofallylmagnesiumchloride was added at rt. The solution was stirred for 1 hbefore it was quenched with MeOH. The solution was diluted with DCM (60mL) and H₂O (20 mL). A lot of precipitates were formed and the solid wasfiltered through a pad of celite. The organic was then separated and theaqueous layer was extracted with 10 mL of EtOAc. The combined organiclayers were concentrated and the residue was purified on 25 g Snapcolumn (0-20% tOAc in Hex, 12 CV) to give(tert-butoxy)-N′-[9-(prop-2-en-1-yl)-6-oxaspiro[4.5]decan-9-yl]carbohydrazide(0.33 g, 68% yield). LCMS m/z 333 (M+Na) observed.

A solution of(tert-butoxy)-N′-[9-(prop-2-en-1-yl)-6-oxaspiro[4.5]decan-9-yl]carbohydrazide(0.33 g, 1.06 mmol) in 4 mL of EtOAc was added 4M HCl in dioxane at rt.The solution was stirred at rt until reaction completion, monitored byLC-MS (30 h). The solvent was then removed to give[9-(prop-2-en-1-yl)-6-oxaspiro[4.5]decan-9-yl]hydrazine (250 mg). LCMSm/z 211.1 (M+1) observed.

A solution of [9-(prop-2-en-1-yl)-6-oxaspiro[4.5]decan-9-yl]hydrazine(250 mg, 1.0 mmol) in 4 mL of i-PrOH were added Et3N and3-dimethylaminoacrolein. The solution was refluxed for 3 h and then at50° C. for 2 d. The solvent removed and the residue was purified on 25 gBiotage snap column, eluted with 0-18% EtOAc in Hex (12 CV) to give1-[9-(prop-2-en-1-yl)-6-oxaspiro[4.5]decan-9-yl]-1H-pyrazole (80 mg, 31%yield).

LCMS m/z 247.1 (M+1) observed.

To a solution of1-[9-(prop-2-en-1-yl)-6-oxaspiro[4.5]decan-9-yl]-1H-pyrazole (80 mg,0.32 mmol) in DCM (5 mL) at −78° C. was bubbled with O₃ until thesolution turned blue. The resulting solution was bubbled with N₂ for 5min. To it was added PPh3 (168 mg, 0.64 mmol). And the solution wasstirred for 4 h at rt. After removal of the solvent, the residue waspurified by flash column chromatography to give2-[9-(1H-pyrazol-1-yl)-6-oxaspiro[4.5]decan-9-yl]acetaldehyde (15 mg,23% yield). LCMS m/z 249 (M+1) observed.

To a mixture of2-[9-(1H-pyrazol-1-yl)-6-oxaspiro[4.5]decan-9-yl]acetaldehyde (15 mg,0.06 mmol) and thiophen-2-ylmethanamine (19 uL, 0.18 mmol) was stirredat rt for 1 h before NaBH(OAc)₃ (25.4 mg, 0.12 mmol) was added. Thesolution stirred overnight. After removal of solvent, the residue waspurified by HPLC to provide{2-[9-(1H-pyrazol-1-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl}(thiophen-2-ylmethyl)amine(17 mg, 61% yield) as a TFA salt. LCMS m/z 346 (M+1) observed.

Example 10 Basic Procedure for Making Compounds of the Formula

Following Scheme 82-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethan-1-amine, whichcan be prepared by following a sequence as described for Compound 81(Compound 4) and a sequence similar to for Intermediate 11 reacts withan appropriately substituted heteroaromatic aldehyde or appropriatelysubstituted aromatic aldehyde (1 equivalent) in the presence of anorganic solvent (i.e. DCM, MeOH, EtOH) to form a corresponding imine,which is reduced by an appropriate reducing agent the compound. The(R)_(n) and the R_(m) refers to the optional substituents Additionally,the phenyl groups can be replaced with other cycles or aryl groups asdescribed herein.

Example 11 Basic Procedures for Making Compounds of the Formula

Following Scheme 9, 9-1, which can be prepared by following a sequencedescribed for Compound 81 (Compound 4) and a sequence similar to forIntermediate 11, reacts with an appropriately substituted heteroaromaticaldehyde or appropriately substituted aromatic aldehyde (1 equivalent)in the presence of an organic solvent (i.e. DCM, MeOH, EtOH and etc) toform a corresponding imine, which is reduced by an appropriate reducingagent (i.e. NaBH₄) to give the compound. The (R)_(n) and the R_(m)refers to the optional substituents Additionally, the phenyl groups canbe replaced with other cycles or aryl groups as described herein.

Example 12 Opioid Receptor Ligands

The opioid receptor ligands and compounds listed in the following tablescan be or were prepared according to the procedures described above fromappropriate starting materials and appropriate reagents. Compounds thathave been made lists NMR data and prophetic examples do not list NMRdata.

TABLE 1 Compounds with chemical name and characterization data MS (m/z)Compound. Name [M + H]⁺ 1H NMR 1 2-[9-(pyridin-2-yl)-6- 261.1 δ 8.58(ddd, J = 4.8, 1.9, 0.9, 1H), 7.63 (m, 1H), oxaspiro[4.5]decan-9- 7.30(m, 1H), 7.12 (ddd, J = 7.4, 4.8, 1.0, 1H), 3.76 (m, yl]ethan-1-amine2H), 2.55 (td, J = 11.6, 5.1, 1H), 2.46 (ddd, J = 13.7, 5.1, 2.7, 1H),2.37 (dd, J = 13.7, 2.1, 1H), 2.14 (td, J = 11.6, 5.0, 1H), 1.92 (m,2H), 1.70 (m, 4H), 1.46 (m, 4H), 1.13 (m, 1H), 0.71 (dt, J = 13.4, 8.8,1H). 2 2-[(9R)-9-(pyridin-2-yl)- 261.2 δ 8.58 (ddd, J = 4.8, 1.7, 0.7,1H), 7.64 (td, J = 7.8, 6-oxaspiro[4.5]decan- 1.9, 1H), 7.28 (m, 1H),7.12 (ddd, J = 7.4, 4.8, 0.9, 9- 1H), 3.76 (m, 2H), 2.55 (m, 1H), 2.46(ddd, J = 13.7, yl]ethan-1-amine 5.1, 2.7, 1H), 2.37 (m, 1H), 2.14 (m,1H), 1.91 (m, 2H), 1.71 (m, 4H), 1.47 (m, 4H), 1.13 (m, 1H), 0.71 (m,1H). 3 2-[9-(2-aminoethyl)-6- 277.1 δ 7.60 (d, J = 6.8, 1H), 7.60 (d, J= 6.8, 1H), 7.21 (s, oxaspiro[4.5]decan-9- 2H), 6.79 (d, J = 332.9, 3H),6.54 (m, 5H), 6.37 (s, yl]pyridin-4-ol 1H), 6.29 (d, J = 6.5, 1H), 5.97(m, 6H), 4.84 (d, J = 169.9, 3H), 3.69 (dt, J = 23.7, 11.7, 3H), 3.69(dt, J = 23.7, 11.7, 3H), 3.40 (s, 2H), 3.40 (s, 2H), 2.64 (s, 1H), 2.64(s, 1H), 2.32 (d, J = 12.0, 1H), 2.26 (dd, J = 46.7, 13.0, 2H), 2.20 (d,J = 13.9, 1H), 2.09 (d, J = 13.8, 1H), 2.09 (d, J = 13.8, 1H), 1.84 (t,J = 15.9, 2H), 1.60 (m, 15H), 1.55 (m, 11H), 0.89 (m, 2H), 0.89 (m, 1H).4 6-[9-(2-aminoethyl)-6- 277.1 δ 8.05 (m, 1H), 7.01 (d, J = 8.6, 1H),6.87 (dd, J = 8.6, oxaspiro[4.5]decan-9- 2.9, 1H), 5.37 (s, 2H), 3.66(dd, J = 13.7, 7.2, 2H), yl]pyridin-3-ol 2.60 (ddd, J = 12.3, 10.1, 5.6,1H), 2.22 (m, 3H), 1.88 (tt, J = 10.0, 7.9, 1H), 1.77 (d, J = 13.6, 1H),1.58 (m, 4H), 1.37 (m, 5H), 1.08 (dd, J = 15.4, 4.9, 1H), 0.63 (dt, J =13.7, 8.9, 1H). 5 6-[9-(2-aminoethyl)-6- 277.1 δ 7.38 (dd, J = 9.0, 7.1,1H), 6.40 (d, J = 9.0, 1H), oxaspiro[4.5]decan-9- 6.09 (d, J = 7.1, 1H),5.28 (s, 1H), 3.73 (s, 2H), yl]pyridin-2-ol 2.69 (m, 1H), 2.37 (m, 2H),2.13 (m, 2H), 1.66 (m, 12H), 0.97 (dt, J = 12.4, 7.6, 1H). 62-[(9R)-9-(2- 277.1 δ 8.23 (m, 1H), 7.31 (dd, J = 5.8, 2.0, 2H), 7.23(m, aminoethyl)-6- 1H), 4.03 (s, 2H), 3.81 (s, 2H), 3.27 (d, J = 13.9,1H), oxaspiro[4.5]decan-9- 2.95 (td, J = 12.8, 5.1, 1H), 2.65 (td, J =11.8, 5.1, yl]-1-oxidopyridin-1- 1H), 2.25 (s, 2H), 1.65 (ddd, J = 38.7,17.6, 11.7, 9H), ium 1.24 (s, 1H), 0.84 (dt, J = 13.1, 8.8, 1H). 7benzyl({2-[1-(4- 312.2 δ 9.72 (t, J = 1.5, 1H), 7.91 (m, 2H), 7.23 (m,3H), fluorophenyl)cyclohexyl]ethyl})amine 7.06 (m, 2H), 6.92 (m, 2H),2.91 (t, J = 6.9, 2H), 2.44 (m, 4H), 2.09 (dd, J = 13.2, 5.3, 2H), 1.68(m, 4H), 1.46 (m, 1H), 1.33 (dd, J = 15.4, 6.7, 4H). 8 benzyl({2-[4-(4-314.2 δ 7.38-7.16 (m, 7H), 7.09-6.99 (m, 2H), fluorophenyl)oxan-4- 3.79(ddd, J = 11.5, 5.7, 3.6, 2H), 3.64 (s, 2H), 3.56 (ddd, J = 11.6,yl]ethyl})amine 8.8, 2.8, 2H), 2.39-2.29 (m, 2H), 2.24-2.01 (m, 4H),1.86 (ddd, J = 13.8, 7.9, 3.5, 2H). 9 [(2- 324.2 δ 7.16 (m, 8H), 3.79(ddd, J = 11.5, 5.2, 3.8, 2H), methylphenyl)methyl]({2- 3.58 (m, 4H),2.41 (m, 2H), 2.36 (s, 3H), 2.27 (s, 3H), [4-(4- 2.16 (m, 2H), 1.86(ddd, J = 12.3, 8.6, 4.6, 4H), 1.58 (s, methylphenyl)oxan-4- 1H)yl]ethyl})amine 10 N-{2-[2,2-dimethyl-4- 324.3 δ 7.25 (dt, J = 5.9, 2.9,3H), 7.11 (m, 2H), 6.98 (dd, J = 25.0, (4-methylphenyl)oxan- 8.2, 4H),3.65 (dd, J = 8.9, 6.7, 2H), 2.95 (d, J = 4.6, 4- 1H), 2.50 (d, J = 4.7,1H), 2.23 (s, 3H), 2.10 (d, J = 13.9, yl]ethyl}aniline 1H), 1.89 (m,3H), 1.43 (m, 2H), 1.21 (m, 1H), 1.05 (s, 3H), 0.53 (s, 3H). 112-[({2-[4-(4- 326.2 δ 7.15 (m, 5H), 6.88 (dd, J = 7.4, 1.3, 1H), 6.79(dd, J = 8.1, methylphenyl)oxan-4- 1.0, 1H), 6.73 (td, J = 7.4, 1.1,1H), 3.76 (m, yl]ethyl}amino)methyl]phenol 4H), 3.54 (ddd, J = 11.7,9.4, 2.5, 2H), 2.37 (m, 5H), 2.13 (m, 2H), 1.82 (m, 4H) 12 2-[({2-[4-(4-330.2 δ 8.26 (s, 2H), 7.07 (m, 3H), 6.95 (dd, J = 14.3, 5.8,fluorophenyl)oxan-4- 2H), 6.86 (d, J = 6.3, 1H), 6.78 (d, J = 8.1, 1H),6.71 (t, yl]ethyl}amino)methyl]phenol J = 7.4, 1H), 3.96 (d, J = 7.0,2H), 3.80 (s, 2H), 3.64 (dt, J = 8.8, 3.9, 2H), 3.41 (t, J = 9.3, 2H),2.45 (s, 2H), 1.95 (d, J = 14.7, 2H), 1.85 (m, 2H), 1.67 (m, 2H). 13benzyl({2-[3-(pyridin-2- 337.1 δ 9.76 (s, 2H), 8.59 (d, J = 4.7, 1H),8.11 (t, J = 7.8, yl)-1- 1H), 7.69 (d, J = 8.1, 1H), 7.63-7.52 (m, 1H),7.35 (s, oxaspiro[4.4]nonan-3- 5H), 4.13 (d, J = 9.7, 1H), 4.03 (s, 2H),3.91 (d, J = 9.7, yl]ethyl})amine 1H), 2.92 (d, J = 26.5, 2H), 2.53(ddd, J = 14.6, 9.5, 5.4, 1H), 2.38 (dd, J = 19.0, 8.5, 2H), 2.28 (d, J= 13.6, 1H), 1.99-1.81 (m, 1H), 1.84-1.52 (m, 6H), 1.51-1.35 (m, 1H). 14benzyl({2-[2,2- 338.3 δ 8.54 (d, J = 226.0, 2H), 7.22 (q, J = 6.7, 3H),dimethyl-4-(4- 7.03 (dd, J = 19.0, 8.3, 6H), 6.23 (d, J = 186.3, 2H),methylphenyl)oxan-4- 3.69 (m, 4H), 2.66 (s, 1H), 2.25 (s, 4H), 2.10 (dd,J = 22.7, yl]ethyl})amine 13.3, 2H), 1.83 (m, 1H), 1.64 (m, 1H), 1.49(m, 2H), 1.11 (s, 3H), 0.57 (s, 3H). 15 {2-[2,2-dimethyl-4-(4- 339.3 δ8.48 (dd, J = 5.2, 0.9, 1H), 8.26 (s, 1H), 7.98 (dd, J = 7.8,methylphenyl)oxan-4- 1.6, 1H), 7.59 (d, J = 7.9, 1H), 7.54 (m, 1H),yl]ethyl}(pyridin-2- 7.07 (s, 4H), 4.17 (q, J = 13.9, 2H), 3.73 (m, 2H),ylmethyl)amine 2.88 (d, J = 4.8, 1H), 2.42 (d, J = 4.8, 1H), 2.21 (m,4H), 2.10 (dd, J = 13.9, 2.1, 1H), 2.00 (d, J = 4.6, 1H), 1.78 (d, J =4.6, 1H), 1.58 (m, 2H), 1.12 (s, 3H), 0.59 (s, 3H). 16{2-[2,2-dimethyl-4-(4- 339.3 δ 8.92 (s, 1H), 8.52 (s, 1H), 8.25 (d, J =8.0, 1H), methylphenyl)oxan-4- 7.67 (m, 1H), 7.08 (m, 4H), 5.92 (s, 4H),4.09 (s, 2H), yl]ethyl}(pyridin-3- 3.71 (m, 2H), 2.85 (dd, J = 12.0,7.9, 1H), 2.34 (m, 1H), ylmethyl)amine 2.23 (m, 4H), 2.10 (d, J = 13.9,1H), 1.94 (m, 1H), 1.74 (dd, J = 12.5, 4.3, 1H), 1.55 (m, 2H), 1.10 (s,3H), 0.57 (s, 3H). 17 [(2- 340.2 δ 7.21 (m, 1H), 7.13 (s, 4H), 7.07 (dd,J = 7.4, 1.7, methoxyphenyl)methyl]({2- 1H), 6.84 (ddd, J = 12.1, 9.3,4.6, 2H), 3.78 (m, 5H), [4-(4- 3.63 (s, 2H), 3.54 (ddd, J = 11.6, 9.1,2.7, 2H), methylphenyl)oxan-4- 2.38 (d, J = 1.3, 1H), 2.32 (m, 5H), 2.10(m, 2H), 1.84 (m, yl]ethyl})amine 4H) 18 (furan-3-ylmethyl)({2- 341.1 δ8.72 (d, J = 4.6, 1H), 8.23 (t, J = 7.3, 1H), [(9R)-9-(pyridin-2-yl)-6-7.84-7.57 (m, 2H), 7.46 (s, 1H), 7.38 (t, J = 1.6, 1H),oxaspiro[4.5]decan-9- 7.28 (s, 1H), 3.89 (s, 2H), 3.82 (dt, J = 12.4,4.2, 1H), yl]ethyl})amine 3.72 (dd, J = 16.1, 6.2, 1H), 2.96 (d, J =4.4, 1H), 2.40 (ddd, J = 36.0, 24.7, 12.8, 4H), 2.20 (dd, J = 12.7, 4.8,1H), 2.01 (d, J = 14.2, 1H), 1.95-1.77 (m, 2H), 1.69 (dd, J = 9.6, 4.4,1H), 1.63-1.39 (m, 4H), 1.21-1.08 (m, 1H), 0.91-0.60 (m, 1H). 19(1H-imidazol-2- 341.1 δ 8.70 (d, J = 5.1, 1H), 8.40 (t, J = 7.9, 1H),7.92 (d, J = 8.2, ylmethyl)({2-[(9R)-9- 1H), 7.87-7.74 (m, 1H), 7.31 (d,J = 18.0, 2H), (pyridin-2-yl)-6- 4.66 (d, J = 14.3, 1H), 4.49 (d, J =14.3, 1H), oxaspiro[4.5]decan-9- 4.02-3.81 (m, 1H), 3.74 (d, J = 9.7,1H), 3.10 (d, J = 4.9, yl]ethyl})amine 1H), 2.84-2.48 (m, 2H), 2.37 (t,J = 12.7, 3H), 2.17-2.00 (m, 1H), 2.00-1.82 (m, 2H), 1.70 (s, 1H),1.65-1.41 (m, 4H), 1.21 (s, 1H), 0.82 (d, J = 13.1, 1H). 20(1,3-oxazol-4- 342.1 δ 8.77 (dd, J = 5.5, 1.4, 1H), 8.26 (td, J = 8.0,1.7, 1H), ylmethyl)({2-[(9R)-9- 7.90 (s, 1H), 7.82 (s, 1H), 7.79-7.60(m, 2H), 4.08 (s, (pyridin-2-yl)-6- 2H), 3.86 (d, J = 12.9, 1H),3.81-3.66 (m, 1H), oxaspiro[4.5]decan-9- 3.13 (d, J = 5.6, 1H),2.76-2.60 (m, 1H), 2.48 (s, 1H), yl]ethyl})amine 2.42-2.25 (m, 3H),2.16-2.01 (m, 1H), 1.89 (dd, J = 9.6, 4.0, 2H), 1.79-1.63 (m, 1H),1.63-1.35 (m, 4H), 1.19 (s, 1H), 0.80 (d, J = 13.2, 1H). 21{2-[3-(pyridin-2-yl)-1- 343 δ 10.01 (s, 3H), 8.62 (d, J = 4.5, 1H), 8.11(td, J = 8.0, oxaspiro[4.4]nonan-3- 1.4, 1H), 7.70 (d, J = 8.1, 1H),7.63-7.46 (m, 1H), yl]ethyl}(thiophen-2- 7.33 (dd, J = 5.1, 1.0, 1H),7.16 (d, J = 2.8, 1H), ylmethyl)amine 7.00 (dd, J = 5.1, 3.6, 1H), 4.29(s, 2H), 4.14 (d, J = 9.7, 1H), 3.92 (d, J = 9.7, 1H), 2.97 (qd, J =18.1, 12.2, 2H), 2.53 (ddd, J = 14.4, 9.0, 5.7, 1H), 2.45-2.21 (m, 3H),2.00-1.82 (m, 1H), 1.67 (tt, J = 22.6, 8.0, 6H), 1.44 (dd, J = 14.3,10.0, 1H). 22 {2-[3-(pyridin-2-yl)-1- 343 δ 11.15 (s, 2H), 9.70 (s, 2H),8.64 (d, J = 4.4, 1H), oxaspiro[4.4]nonan-3- 8.17 (td, J = 8.0, 1.5,1H), 7.74 (d, J = 8.1, 1H), yl]ethyl}(thiophen-3- 7.63 (dd, J = 6.7,5.7, 1H), 7.40 (dd, J = 2.8, 1.1, 1H), ylmethyl)amine 7.33 (dd, J = 5.0,3.0, 1H), 7.10 (dd, J = 5.0, 1.2, 1H), 4.23-4.07 (m, 3H), 3.94 (d, J =9.8, 1H), 2.90 (d, J = 33.7, 2H), 2.67-2.50 (m, 1H), 2.50-2.24 (m, 3H),1.91 (dd, J = 13.7, 4.9, 1H), 1.83-1.52 (m, 6H), 1.43 (td, J = 7.7, 3.9,1H). 23 (cyclopentylmethyl)({2- 343.3 δ 8.77 (d, J = 4.6, 2H), 8.26 (t,J = 7.6, 1H), [(9R)-9-(pyridin-2-yl)-6- 7.89-7.60 (m, 2H), 3.85 (dd, J =8.5, 4.2, 1H), 3.73 (t, J = 10.1, oxaspiro[4.5]decan-9- 1H), 3.00 (s,1H), 2.81 (s, 2H), 2.42 (dt, J = 23.0, yl]ethyl})amine 9.5, 4H), 2.25(t, J = 10.8, 1H), 2.19-1.98 (m, 2H), 1.98-1.33 (m, 13H), 1.16 (s, 3H),0.76 (dt, J = 13.1, 8.9, 1H). 24 {2-[2,2-dimethyl-4-(4- 344.2 δ 8.87 (d,J = 194.4, 2H), 3.91 (s, 3H), 3.69 (m, 2H), methylphenyl)oxan-4- 2.66(d, J = 7.9, 1H), 2.24 (m, 4H), 2.10 (ddd, J = 30.6,yl]ethyl}(thiophen-2- 14.0, 2.1, 2H), 1.84 (td, J = 12.5, 4.9, 1H),ylmethyl)amine 1.65 (m, 1H), 1.49 (m, 2H), 1.11 (d, J = 6.1, 3H), 0.57(s, 3H). 25 {2-[4-(4- 344.2 δ 7.20 (ddd, J = 7.6, 4.8, 2.0, 3H), 7.03(m, 3H), fluorophenyl)oxan-4- 6.84 (ddd, J = 11.7, 9.1, 4.5, 2H), 3.77(m, 5H), 3.61 (s, yl]ethyl}[(2- 2H), 3.54 (ddd, J = 11.6, 8.8, 2.8, 2H),2.27 (m, 2H), methoxyphenyl)methyl]amine 2.08 (m, 2H), 1.84 (ddd, J =10.5, 8.4, 3.0, 4H), 1.58 (s, 1H) 26 {2-[9-(1H-pyrazol-1-yl)- 346 δ 9.87(s, 1H), 9.00 (d, J = 145.4, 2H), 7.46 (dd, J = 12.7,6-oxaspiro[4.5]decan- 2.1, 2H), 7.28 (dd, J = 5.1, 1.1, 1H), 7.01 (d, J= 0.8, 9- 1H), 6.93 (dd, J = 5.1, 3.5, 1H), 6.34-6.24 (m,yl]ethyl}(thiophen-2- 1H), 5.22 (s, 1H), 4.10 (q, J = 14.2, 2H), 3.68(d, J = 2.7, ylmethyl)amine 2H), 2.94 (s, 1H), 2.50 (s, 1H), 2.31 (s,2H), 2.24-2.08 (m, 1H), 1.99 (dt, J = 14.7, 7.3, 1H), 1.93-1.76 (m, 2H),1.75-1.63 (m, 1H), 1.57 (ddd, J = 23.2, 14.0, 8.1, 1H), 1.51 (s, 4H),1.17-1.04 (m, 1H), 0.69 (dt, J = 13.3, 8.7, 1H). 27 benzyl({2-[(9S)-9-351.1 δ 8.67 (d, J = 4.7, 1H), 8.17 (t, J = 7.7, 1H), 7.64 (m,(pyridin-2-yl)-6- 2H), 7.35 (m, 5H), 6.51 (s, 4H), 4.72 (s, 1H), 3.94(s, oxaspiro[4.5]decan-9- 2H), 3.75 (m, 2H), 2.95 (s, 1H), 2.49 (s, 1H),2.33 (m, yl]ethyl})amine 3H), 2.19 (m, 1H), 1.98 (d, J = 14.1, 1H), 1.81(dt, J = 13.4, 7.5, 2H), 1.68 (m, 1H), 1.49 (ddd, J = 20.8, 14.7, 7.2,4H), 1.15 (s, 1H), 0.75 (m, 1H). 28 benzyl({2-[(9R)-9- 351.1 δ 8.61 (s,1H), 8.18 (t, J = 7.7, 1H), 7.65 (m, 2H), (pyridin-2-yl)-6- 7.26 (m,5H), 6.90 (d, J = 26.0, 4H), 3.88 (s, 2H), 3.72 (d, J = 12.7,oxaspiro[4.5]decan-9- 1H), 3.60 (t, J = 10.0, 1H), 2.90 (s, 1H),yl]ethyl})amine 2.39 (d, J = 34.6, 2H), 2.20 (t, J = 13.3, 3H), 1.92 (d,J = 14.8, 2H), 1.75 (m, 2H), 1.59 (d, J = 4.9, 1H), 1.41 (m, 4H), 1.08(s, 1H), 0.68 (dt, J = 13.2, 9.0, 1H). 29 benzyl({2-[3-(pyridin-2- 351.1δ 9.67 (s, 2H), 8.61 (s, 1H), 8.19 (t, J = 7.5, 1H), yl)-1- 7.80 (d, J =8.1, 1H), 7.64 (s, 1H), 7.36 (s, 5H), 4.22 (d, J = 10.0,oxaspiro[4.5]decan-3- 1H), 4.05 (s, 2H), 3.98 (d, J = 10.0, 1H), 3.00(s, yl]ethyl})amine 1H), 2.84 (s, 1H), 2.64 (s, 1H), 2.39 (d, J = 8.7,1H), 2.18 (d, J = 13.6, 1H), 2.09 (d, J = 13.6, 1H), 1.75-1.52 (m, 4H),1.33 (dd, J = 28.9, 16.2, 7H). 30 benzyl({2-[9-(pyridin-2- 351.2 δ 8.49(s, 1H), 8.03 (s, 1H), 7.53 (d, J = 8.0, 2H), yl)-6- 7.18 (m, 5H), 3.82(s, 2H), 3.63 (s, 1H), 3.53 (dd, J = 23.8, oxaspiro[4.5]decan-9- 13.7,1H), 2.84 (s, 1H), 2.38 (s, 1H), 2.27 (d, J = 7.4, yl]ethyl})amine 1H),2.13 (d, J = 14.1, 3H), 1.84 (d, J = 14.2, 1H), 1.67 (m, 2H), 1.52 (d, J= 5.0, 1H), 1.32 (m, 4H), 1.01 (s, 1H), 0.61 (dt, J = 13.0, 8.9, 1H). 31{2-[2,2-dimethyl-4-(4- 352.2 δ 7.09 (d, J = 8.3, 2H), 7.02 (ddd, J =8.1, 6.1, 3.3, methylphenyl)oxan-4- 6H), 3.69 (m, 2H), 3.47 (s, 2H),2.41 (td, J = 10.8, 5.4, yl]ethyl}[(2- 1H), 2.25 (m, 4H), 2.11 (m, 5H),1.75 (ddd, J = 13.2, methylphenyl)methyl]amine 10.4, 5.2, 1H), 1.56 (m,4H), 1.11 (s, 3H), 0.59 (s, 3H). 32 {2-[2,2-dimethyl-4-(4- 352.3 δ 9.13(s, 1H), 8.69 (s, 1H), 7.04 (m, 6H), 6.86 (m, methylphenyl)oxan-4- 2H),3.65 (m, 6H), 2.59 (s, 1H), 2.12 (m, 9H), yl]ethyl}[(3- 1.83 (td, J =12.4, 4.5, 1H), 1.64 (m, 1H), 1.48 (m, 2H), methylphenyl)methyl]amine1.10 (s, 3H), 0.57 (s, 3H). 33 {2-[2,2-dimethyl-4-(4- 352.3 δ 8.68 (d, J= 205.9, 2H), 7.02 (dd, J = 16.8, 9.0, 6H), methylphenyl)oxan-4- 6.93(d, J = 8.1, 2H), 3.67 (dd, J = 6.6, 2.7, 2H), yl]ethyl}[(4- 3.57 (s,2H), 3.44 (s, 3H), 2.61 (s, 1H), 2.25 (d, J = 11.2,methylphenyl)methyl]amine 3H), 2.17 (s, 3H), 2.08 (dd, J = 20.3, 14.0,2H), 1.84 (m, 1H), 1.67 (d, J = 7.6, 1H), 1.48 (m, 2H), 1.09 (s, 3H),0.56 (s, 3H). 34 {2-[2,2-dimethyl-4-(4- 352.3 δ 9.07 (dd, J = 228.2,166.6, 2H), 7.24 (ddd, J = 9.3, methylphenyl)oxan-4- 6.4, 3.4, 3H), 7.15(m, 2H), 6.94 (m, 4H), 3.91 (s, 1H), yl]ethyl}[(1R)-1- 3.61 (dd, J =7.0, 4.0, 2H), 2.42 (d, J = 33.9, 1H), phenylethyl]amine 2.21 (d, J =11.7, 6H), 2.00 (m, 2H), 1.82 (m, 1H), 1.62 (dd, J = 8.6, 4.1, 1H), 1.42(m, 5H), 1.05 (s, 3H), 0.53 (d, J = 3.4, 3H). 35 {2-[2,2-dimethyl-4-(4-352.3 δ 8.92 (dd, J = 238.8, 174.0, 2H), 7.24 (m, 3H),methylphenyl)oxan-4- 7.14 (td, J = 7.5, 2.2, 2H), 6.95 (m, 4H), 3.89 (d,J = 19.3, yl]ethyl}[(1S)-1- 1H), 3.62 (m, 2H), 2.96 (s, 2H), 2.42 (m,1H), 2.21 (d, phenylethyl]amine J = 11.6, 3H), 2.00 (m, 3H), 1.82 (m,1H), 1.63 (m, 1H), 1.40 (m, 5H), 1.06 (s, 3H), 0.53 (d, J = 3.6, 3H). 36benzyl({2-[2,2- 352.3 δ 11.09 (s, 2H), 7.39 (m, 3H), 7.23 (m, 1H), 7.15(m, dimethyl-4-(4- 5H), 4.19 (dd, J = 25.7, 12.6, 1H), 3.91 (dd, J =17.4, methylphenyl)oxan-4- 8.4, 1H), 3.78 (m, 2H), 2.91 (d, J = 127.4,1H), yl]ethyl})methylamine 2.56 (dd, J = 17.7, 7.2, 3H), 2.37 (d, J =4.8, 3H), 2.24 (ddd, J = 22.0, 12.2, 2.2, 3H), 2.05 (m, 1H), 1.88 (td, J= 12.5, 4.7, 1H), 1.64 (m, 2H), 1.21 (s, 3H), 382.30.67 (d, J = 1.2,3H). 37 {2-[2,2-dimethyl-4-(4- 352.3 δ 9.06 (d, J = 128.6, 2H), 7.17 (m,3H), 7.02 (m, 6H), methylphenyl)oxan-4- 3.68 (dd, J = 11.8, 10.1, 2H),2.77 (dt, J = 36.5, 30.4, yl]ethyl}(2- 7H), 2.19 (m, 5H), 1.99 (m, 1H),1.89 (td, J = 12.5, phenylethyl)amine 4.6, 1H), 1.69 (m, 1H), 1.49 (m,2H), 1.00 (s, 3H), 0.52 (s, 3H). 38 (pyrazin-2- 353.1 δ 8.79 (dd, J =5.6, 1.4, 1H), 8.68-8.54 (m, 2H), ylmethyl)({2-[(9R)-9- 8.51 (dd, J =2.3, 1.6, 1H), 8.32 (td, J = 8.0, 1.6, 1H), (pyridin-2-yl)-6- 7.93-7.66(m, 3H), 4.30 (s, 2H), 3.85 (dt, J = 12.3, 4.2, 1H),oxaspiro[4.5]decan-9- 3.72 (t, J = 9.9, 1H), 3.19 (td, J = 11.7, 5.2,1H), yl]ethyl})amine 2.72 (td, J = 11.8, 4.0, 1H), 2.62-2.45 (m, 1H),2.45-2.27 (m, 3H), 2.10 (d, J = 14.2, 1H), 2.00-1.79 (m, 2H), 1.69 (dt,J = 9.9, 6.6, 1H), 1.63-1.41 (m, 4H), 1.19 (dd, J = 12.6, 6.5, 1H), 0.78(dt, J = 13.1, 8.9, 1H). 39 benzyl({2-[2,2-diethyl- 353.3 δ 8.71 (dd, J= 5.5, 1.4, 1H), 8.21 (td, J = 8.0, 1.7, 1H), 4-(pyridin-2-yl)oxan-4-7.67 (m, 2H), 7.33 (m, 5H), 3.95 (s, 2H), 3.79 (m, 1H), yl]ethyl})amine3.67 (d, J = 10.8, 1H), 3.01 (d, J = 5.2, 1H), 2.40 (m, 4H), 2.10 (s,1H), 1.73 (t, J = 16.5, 2H), 1.55 (dd, J = 14.1, 7.5, 1H), 1.39 (dd, J =14.1, 7.4, 1H), 0.81 (m, 5H), 0.56 (t, J = 7.3, 3H). 40benzyl({2-[2,2,6,6- 353.3 δ 8.74-8.62 (m, 1H), 8.24 (td, J = 8.1, 1.5,1H), tetramethyl-4-(pyridin- 7.87 (d, J = 8.2, 1H), 7.76-7.65 (m, 1H),7.47-7.18 (m, 2- 7H), 3.96 (s, 2H), 2.75 (s, 2H), 2.50 (d, J = 14.7,2H), yl)oxan-4- 2.43-2.28 (m, 2H), 1.89 (d, J = 14.8, 2H), 1.30 (s,yl]ethyl})amine 6H), 0.97 (s, 6H). 41 4-[({2-[2,2-dimethyl-4- 354.2 δ8.58 (d, J = 187.3, 2H), 7.05 (q, J = 8.3, 4H), (4-methylphenyl)oxan-6.91 (d, J = 8.3, 2H), 6.58 (d, J = 8.4, 2H), 3.67 (d, J = 10.4, 4- 2H),3.58 (s, 2H), 2.63 (d, J = 18.2, 1H), 2.26 (s, 4H),yl]ethyl}amino)methyl]phenol 2.07 (d, J = 14.3, 4H), 1.84 (t, J = 10.2,1H), 1.49 (d, J = 13.9, 3H), 1.09 (s, 3H), 0.56 (s, 3H). 422-[({2-[2,2-dimethyl-4- 354.3 δ 8.15 (d, J = 107.7, 2H), 7.03 (dt, J =26.2, 8.3, 5H), (4-methylphenyl)oxan- 6.82 (m, 2H), 6.64 (t, J = 7.4,1H), 3.68 (m, 6H), 4- 2.58 (s, 1H), 2.24 (d, J = 6.8, 4H), 2.05 (dd, J =21.0, 14.9, yl]ethyl}amino)methyl]phenol 2H), 1.78 (d, J = 4.4, 1H),1.58 (s, 1H), 1.44 (dd, J = 21.2, 9.8, 2H), 1.10 (d, J = 18.7, 3H), 0.57(d, J = 24.3, 3H). 43 3-[({2-[2,2-dimethyl-4- 354.3 δ 8.50 (d, J =165.4, 2H), 7.02 (m, 5H), 6.68 (d, J = 7.5, (4-methylphenyl)oxan- 2H),6.47 (d, J = 7.4, 1H), 3.67 (d, J = 9.4, 2H), 4- 3.59 (s, 2H), 2.63 (s,2H), 2.23 (s, 4H), 2.09 (dd, J = 27.3, yl]ethyl}amino)methyl]phenol13.5, 2H), 1.84 (d, J = 7.8, 1H), 1.66 (d, J = 8.6, 1H), 1.52 (d, J =13.9, 2H), 1.09 (s, 3H), 0.56 (s, 3H). 44 [(5-methylfuran-2- 355.1 δ8.73 (d, J = 4.2, 1H), 8.18 (td, J = 8.0, 1.5, 1H),yl)methyl]({2-[(9R)-9- 7.80-7.53 (m, 2H), 7.29 (s, 1H), 4.00 (d, J =1.4, 2H), (pyridin-2- 3.83 (dt, J = 12.4, 4.3, 1H), 3.79-3.63 (m, 1H),yl)-6- 3.10-2.86 (m, 1H), 2.64-2.44 (m, 1H), 2.45-2.27 (m,oxaspiro[4.5]decan-9- 3H), 2.27-2.11 (m, 4H), 2.02 (d, J = 14.2, 1H),yl]ethyl})amine 1.95-1.77 (m, 2H), 1.68 (dd, J = 9.5, 4.1, 1H),1.62-1.39 (m, 4H), 1.26-1.05 (m, 1H), 0.77 (dt, J = 13.3, 9.0, 1H). 45[(5-methylfuran-2- 356.1 δ 8.66 (s, 1H), 8.56 (s, 1H), 8.50 (s, 1H),6.27 (d, J = 3.2, yl)methyl]({2-[9- 1H), 6.05-5.83 (m, 1H), 3.94 (d, J =1.9, 2H), (pyrazin-2-yl)-6- 3.85-3.59 (m, 2H), 2.89 (d, J = 5.0, 1H),2.49 (d, J = 5.1, oxaspiro[4.5]decan-9- 1H), 2.38 (t, J = 16.0, 2H),2.24 (s, 4H), 2.02 (dd, yl]ethyl})amine J = 18.2, 6.8, 2H), 1.96-1.88(m, 2H), 1.59-1.37 (m, 5H), 1.09 (s, 1H), 0.66 (d, J = 13.4, 1H). 46benzyl({2-[9-(thiophen- 356.2 δ 9.56 (s, 1H), 9.11 (s, 1H), 7.31 (m,3H), 7.23 (m, 2-yl)-6- 2H), 7.19 (dd, J = 5.1, 1.0, 1H), 6.91 (dd, J =5.1, 3.6, oxaspiro[4.5]decan-9- 1H), 6.74 (d, J = 3.5, 1H), 3.72 (m,4H), 2.74 (m, 1H), yl]ethyl})amine 2.44 (m, 1H), 2.01 (d, J = 13.9, 2H),1.95 (dd, J = 11.7, 5.0, 1H), 1.87 (m, 2H), 1.73 (s, 5H), 1.66 (m, 2H),1.50 (m, 3H), 1.00 (dd, J = 13.6, 8.5, 1H). 47 {2-[2,2-dimethyl-4-(4-356.3 δ 7.15 (m, 1H), 7.06 (m, 5H), 6.94 (dt, J = 18.3, 8.1,methylphenyl)oxan-4- 2H), 3.69 (t, J = 7.7, 2H), 3.60 (s, 2H), 2.44 (dd,J = 11.0, yl]ethyl}[(2- 5.2, 1H), 2.22 (d, J = 20.4, 4H), 2.11 (m, 2H),fluorophenyl)methyl]amine 1.77 (dd, J = 6.6, 4.0, 1H), 1.57 (qd, J =10.9, 5.5, 3H), 1.11 (s, 3H), 0.59 (s, 3H). 48 {2-[2,2-dimethyl-4-(4-356.3 δ 8.79 (d, J = 198.9, 2H), 7.19 (m, 2H), 7.05 (d, J = 8.2,methylphenyl)oxan-4- 2H), 7.00 (d, J = 8.4, 2H), 6.94 (td, J = 8.4, 2.2,yl]ethyl}[(3- 1H), 6.86 (d, J = 7.6, 1H), 6.79 (d, J = 8.9, 1H), 6.36(s, fluorophenyl)methyl]amine 2H), 3.69 (m, 4H), 2.65 (s, 1H), 2.24 (s,3H), 2.11 (ddd, J = 18.3, 15.7, 11.3, 3H), 1.81 (dt, J = 12.3, 6.2, 1H),1.63 (m, 1H), 1.48 (m, 2H), 1.10 (s, 3H), 0.56 (s, 3H). 49{2-[2,2-dimethyl-4-(4- 356.3 δ 8.73 (d, J = 173.6, 2H), 7.03 (m, 6H),6.88 (t, J = 8.5, methylphenyl)oxan-4- 2H), 5.32 (s, 2H), 3.68 (m, 4H),2.61 (s, 1H), yl]ethyl}[(4- 2.24 (s, 3H), 2.11 (m, 3H), 1.78 (dt, J =12.3, 6.2, 1H), fluorophenyl)methyl]amine 1.61 (m, 1H), 1.47 (m, 2H),1.10 (s, 3H), 0.56 (s, 3H). 50 benzyl(2-{9-cyclohexyl- 356.3 δ 9.09 (d,J = 38.9, 2H), 7.35 (m, 5H), 6.43 (s, 2H), 6-oxaspiro[4.5]decan- 3.93(s, 2H), 3.54 (m, 2H), 2.85 (s, 2H), 1.63 (m, 9- 16H), 1.10 (m, 7H),0.84 (q, J = 11.8, 2H). yl}ethyl)amine 51 {2-[3-(pyridin-2-yl)-1- 357 δ9.79 (s, 2H), 8.66 (s, 1H), 8.21 (t, J = 7.5, 1H), oxaspiro[4.5]decan-3-7.80 (d, J = 8.1, 1H), 7.66 (s, 1H), 7.33 (d, J = 5.0, 1H),yl]ethyl}(thiophen-2- 7.16 (s, 1H), 7.06-6.98 (m, 1H), 4.29 (s, 2H),4.23 (d, J = 9.9, ylmethyl)amine 1H), 3.99 (d, J = 10.0, 1H), 3.00 (s,1H), 2.87 (s, 1H), 2.63 (t, J = 9.5, 1H), 2.39 (d, J = 8.6, 1H), 2.20(d, J = 13.5, 1H), 2.10 (d, J = 13.6, 1H), 1.77-1.49 (m, 4H), 1.47-1.19(m, 6H). 52 {2-[3-(pyridin-2-yl)-1- 357 δ 9.72 (s, 2H), 8.64 (s, 1H),8.21 (t, J = 7.5, 1H), oxaspiro[4.5]decan-3- 7.80 (d, J = 8.1, 1H), 7.66(t, J = 5.9, 1H), 7.44-7.31 (m, yl]ethyl}(thiophen-3- 2H), 7.09 (d, J =4.8, 1H), 4.23 (d, J = 9.9, 1H), 4.10 (s, ylmethyl)amine 2H), 3.99 (d, J= 10.0, 1H), 2.95 (s, 1H), 2.80 (s, 1H), 2.64 (s, 1H), 2.39 (d, J = 8.7,1H), 2.21 (d, J = 13.7, 1H), 2.10 (d, J = 13.6, 1H), 1.77-1.50 (m, 4H),1.49-1.22 (m, 6H). 53 {2-[9-(pyridin-2-yl)-6- 357.1 δ 8.67 (d, J = 4.3,1H), 8.14 (s, 1H), 7.66 (d, J = 8.2, oxaspiro[4.5]decan-9- 1H), 7.59 (s,1H), 7.33 (dd, J = 5.1, 1.1, 1H), 7.12 (d, J = 2.7,yl]ethyl}(thiophen-2- 1H), 7.00 (dd, J = 5.1, 3.5, 1H), 4.22 (s, 2H),ylmethyl)amine 3.80 (s, 1H), 3.72 (t, J = 9.8, 1H), 3.33-2.70 (m, 1H),2.70-2.50 (m, 1H), 2.30 (d, J = 14.0, 3H), 2.19 (dd, J = 18.0, 7.1, 1H),1.98 (d, J = 14.1, 1H), 1.83 (d, J = 4.6, 2H), 1.76-1.62 (m, 1H), 1.50(dd, J = 20.1, 13.3, 5H), 1.16 (s, 1H), 0.75 (dt, J = 13.1, 9.1, 1H). 54{2-[(9R)-9-(pyridin-2- 357.2 δ 8.67 (d, J = 4.3, 1H), 8.14 (s, 1H), 7.66(d, J = 8.2, yl)-6- 1H), 7.59 (s, 1H), 7.33 (dd, J = 5.1, 1.1, 1H), 7.12(d, J = 2.7, oxaspiro[4.5]decan-9- 1H), 7.00 (dd, J = 5.1, 3.5, 1H),4.22 (s, 2H), yl]ethyl}(thiophen-2- 3.80 (s, 1H), 3.72 (t, J = 9.8, 1H),3.33-2.70 (m, 1H), ylmethyl)amine 2.70-2.50 (m, 1H), 2.30 (d, J = 14.0,3H), 2.19 (dd, J = 18.0, 7.1, 1H), 1.98 (d, J = 14.1, 1H), 1.83 (d, J =4.6, 2H), 1.76-1.62 (m, 1H), 1.50 (dd, J = 20.1, 13.3, 5H), 1.16 (s,1H), 0.75 (dt, J = 13.1, 9.1, 1H). 55 {2-[(9R)-9-(pyridin-2- 357.2 δ8.73 (d, J = 5.0, 1H), 8.27 (t, J = 7.5, 2H), yl)-6- 7.88-7.62 (m, 2H),7.48-7.23 (m, 1H), 7.04 (dd, J = 4.9, oxaspiro[4.5]decan-9- 1.0, 1H),4.02 (s, 2H), 3.90-3.76 (m, 1H), 3.69 (t, J = 10.0,yl]ethyl}(thiophen-3- 1H), 2.95 (s, 1H), 2.62-2.12 (m, 4H),ylmethyl)amine 2.13-1.95 (m, 1H), 1.95-1.76 (m, 2H), 1.68 (dt, J = 13.5,7.9, 1H), 1.62-1.30 (m, 5H), 1.16 (dd, J = 13.2, 6.6, 1H), 0.76 (dt, J =13.0, 8.9, 1H). 56 {2-[(9R)-9-(pyridin-2- 358 δ 8.77 (d, J = 4.3, 1H),8.27 (t, J = 7.3, 1H), yl)-6- 7.86-7.65 (m, 2H), 7.43 (d, J = 3.1, 1H),7.28 (s, 1H), oxaspiro[4.5]decan-9- 4.56-4.39 (m, 2H), 3.79 (dddd, J =21.9, 19.5, 10.8, 7.1, yl]ethyl}(1,3-thiazol-2- 2H), 3.19 (td, J = 11.5,5.3, 1H), 2.81-2.63 (m, 1H), ylmethyl)amine 2.62-2.43 (m, 1H), 2.43-2.26(m, 3H), 2.14-1.99 (m, 1H), 2.00-1.79 (m, 2H), 1.79-1.63 (m, 1H),1.63-1.38 (m, 4H), 1.20 (dd, J = 13.0, 6.5, 1H), 0.79 (dt, J = 13.0,8.9, 1H). 57 {2-[(9R)-9-(pyridin-2- 358 δ 8.76 (d, J = 4.7, 1H), 8.37(td, J = 8.1, 1.4, 1H), yl)-6- 8.12-7.72 (m, 3H), 7.29 (s, 1H), 4.37 (s,2H), oxaspiro[4.5]decan-9- 3.93-3.58 (m, 2H), 3.05 (td, J = 11.7, 5.1,1H), 2.66-2.43 (m, yl]ethyl}(1,3-thiazol-5- 2H), 2.42-2.22 (m, 3H),2.18-1.96 (m, 1H), ylmethyl)amine 1.96-1.79 (m, 2H), 1.79-1.39 (m, 5H),1.18 (dd, J = 12.1, 5.5, 1H), 0.77 (dt, J = 12.9, 8.9, 1H). 58{2-[9-(pyrazin-2-yl)-6- 358 δ 8.63 (s, 1H), 8.55 (s, 1H), 8.49 (d, J =2.3, 1H), oxaspiro[4.5]decan-9- 7.33 (dd, J = 5.1, 1.1, 1H), 7.08 (d, J= 2.6, 1H), yl]ethyl}(thiophen-2- 7.05-6.97 (m, 1H), 3.73 (d, J = 36.7,2H), 3.17-2.73 (m, 1H), ylmethyl)amine 2.54-2.43 (m, 1H), 2.35 (d, J =13.0, 2H), 2.24-2.11 (m, 1H), 2.05-2.15 (m, 4H), 1.51 (s, 5H), 1.14-1.01(m, 1H), 0.66 (s, 1H). 59 {2-[2,2-diethyl-4- 359.2 δ 8.72 (dd, J = 5.5,1.4, 1H), 8.21 (td, J = 8.0, 1.7, 1H), (pyridin-2-yl)oxan-4- 7.68 (m,2H), 7.35 (dd, J = 2.9, 1.2, 1H), 7.30 (m, 2H), yl]ethyl}(thiophen-3-7.04 (dd, J = 5.0, 1.3, 1H), 4.02 (s, 2H), 3.80 (dd, J = 10.0,ylmethyl)amine 6.3, 1H), 3.68 (d, J = 10.8, 1H), 3.00 (m, 1H), 2.42 (m,4H), 2.08 (d, J = 4.4, 1H), 1.78 (s, 1H), 1.71 (d, J = 14.5, 1H), 1.56(dd, J = 14.1, 7.5, 1H), 1.40 (dd, J = 14.1, 7.4, 1H), 0.81 (m, 5H),0.57 (t, J = 7.3, 3H). 60 {2-[2,2-diethyl-4- 359.2 δ 8.70 (dd, J = 5.4,1.4, 1H), 8.15 (d, J = 1.6, 1H), (pyridin-2-yl)oxan-4- 7.66 (d, J = 8.2,1H), 7.60 (dd, J = 6.7, 5.5, 1H), 7.33 (dd, J = 5.1,yl]ethyl}(thiophen-2- 1.2, 1H), 7.11 (d, J = 2.6, 1H), 6.99 (dd, J =5.1, ylmethyl)amine 3.6, 1H), 3.73 (d, J = 44.0, 4H), 4.02 (s, 2H), 3.80(dd, J = 10.0, 6.3, 1H), 3.68 (d, J = 10.8, 1H), 3.00 (m, 1H), 2.42 (m,4H), 2.08 (d, J = 4.4, 1H), 1.78 (s, 1H), 1.71 (d, J = 14.5, 1H), 1.56(dd, J = 14.1, 7.5, 1H), 1.40 (dd, J = 14.1, 7.4, 1H), 0.81 (m, 5H),0.57 (t, J = 7.3, 3H). 61 {2-[2,2,6,6- 359.2 δ 8.63 (dd, J = 5.6, 1.3,1H), 8.18 (td, J = 8.1, 1.6, 1H), tetramethyl-4-(pyridin- 7.81 (d, J =8.2, 1H), 7.63 (dd, J = 6.8, 5.8, 1H), 2-yl)oxan-4- 7.36-7.16 (m, 2H),7.05-6.96 (m, 2H), 6.88 (dd, J = 5.1, yl]ethyl}(thiophen-2- 3.6, 2H),4.13 (s, 2H), 2.80-2.60 (m, 2H), 2.43 (d, J = 14.7, ylmethyl)amine 2H),2.33-2.17 (m, 2H), 1.81 (d, J = 14.8, 2H), 1.21 (d, J = 12.2, 6H), 0.89(s, 6H). 62 {2-[2,2,6,6- 359.2 δ 8.62 (dd, J = 5.6, 1.4, 1H), 8.19 (td,J = 8.0, 1.7, 1H), tetramethyl-4-(pyridin- 7.81 (d, J = 8.2, 2H),7.67-7.60 (m, 1H), 7.27 (dd, J = 2.9, 2-yl)oxan-4- 1.2, 1H), 7.23-7.17(m, 2H), 6.95 (dd, J = 5.0, yl]ethyl}(thiophen-3- 1.3, 1H), 3.95 (s,2H), 2.62 (d, J = 8.1, 2H), 2.41 (d, J = 14.7, ylmethyl)amine 2H),2.34-2.08 (m, 2H), 1.82 (d, J = 14.8, 2H), 1.21 (d, J = 13.1, 6H), 0.89(s, 6H). 63 {2-[9-(thiophen-2-yl)-6- 362.2 δ 9.60 (s, 1H), 9.27 (s, 1H),7.29 (dd, J = 5.1, 1.1, oxaspiro[4.5]decan-9- 2H), 7.21 (dd, J = 5.1,1.0, 1H), 7.03 (d, J = 2.6, 1H), yl]ethyl}(thiophen-2- 6.94 (ddd, J =9.9, 5.1, 3.6, 2H), 6.77 (dd, J = 3.6, 1.1, ylmethyl)amine 1H), 4.03 (s,2H), 3.74 (m, 2H), 2.80 (td, J = 11.9, 4.9, 1H), 2.50 (td, J = 11.8,5.0, 1H), 1.96 (m, 4H), 1.71 (m, 4H), 1.48 (m, 6H), 1.00 (dt, J = 12.7,8.1, 1H). 64 {2-[9-(thiophen-2-yl)-6- 362.2 δ 9.46 (s, 1H), 9.23 (s,1H), 7.27 (m, 2H), 7.21 (dd, J = 5.1, oxaspiro[4.5]decan-9- 1.0, 1H),7.00 (dt, J = 7.5, 4.4, 1H), 6.93 (dd, J = 5.1, yl]ethyl}(thiophen-3-3.5, 1H), 6.75 (dd, J = 3.6, 1.1, 1H), 3.85 (s, 2H), ylmethyl)amine 3.74(m, 2H), 2.73 (m, 1H), 2.43 (s, 1H), 2.12 (m, 1H), 2.03 (m, 2H), 1.96(dd, J = 12.4, 7.6, 1H), 1.87 (m, 2H), 1.70 (m, 3H), 1.48 (m, 5H), 1.00(dt, J = 12.8, 8.1, 1H). 65 (cyclopentylmethyl)({2- 362.3 δ 9.23 (m,1H), 8.73 (m, 1H), 7.25 (dd, J = 8.9, 5.2, [2,2-diethyl-4-(4- 2H), 7.07(t, J = 8.6, 2H), 3.73 (d, J = 10.9, 2H), fluorophenyl)oxan-4- 2.69 (s,2H), 2.10 (m, 4H), 1.78 (d, J = 18.1, 3H), 1.64 (m, yl]ethyl})amine 7H),1.38 (s, 2H), 1.28 (s, 1H), 1.10 (d, J = 16.3, 3H), 0.84 (s, 4H), 0.53(s, 3H). 66 (cyclopentylmethyl)({2- 362.3 δ 8.64 (s, 2H), 7.22 (dd, J =8.9, 5.1, 2H), 6.95 (t, J = 8.6, [4-(4-fluorophenyl)- 2H), 3.25 (s, 2H),2.61 (s, 2H), 2.43 (s, 2H), 2,2,6,6- 2.24 (d, J = 14.3, 2H), 1.91 (m,2H), 1.68 (m, 2H), 1.60 (d, J = 14.3, tetramethyloxan-4- 2H), 1.49 (m,4H), 1.18 (s, 6H), 1.03 (dd, J = 12.4, yl]ethyl})amine 7.3, 2H), 0.93(s, 6H). 67 (2-{9-cyclohexyl-6- 362.3 δ 9.21 (d, J = 25.7, 2H), 7.33(dd, J = 5.1, 1.1, 2H), oxaspiro[4.5]decan-9- 7.14 (d, J = 2.7, 1H),7.00 (dd, J = 5.1, 3.6, 1H), yl}ethyl)(thiophen-2- 4.19 (s, 2H), 3.56(m, 2H), 2.92 (s, 2H), 1.65 (m, 17H), ylmethyl)amine 1.12 (m, 7H), 0.87(dd, J = 23.8, 11.9, 2H). 68 (2-{9-cyclohexyl-6- 362.3 δ 9.07 (d, J =31.8, 2H), 7.37 (ddd, J = 7.9, 3.9, 2.1, oxaspiro[4.5]decan-9- 2H), 7.10(dd, J = 5.0, 1.3, 1H), 6.37 (s, 2H), 4.04 (s, yl}ethyl)(thiophen-3-2H), 3.55 (m, 2H), 2.87 (s, 2H), 1.64 (m, 16H), ylmethyl)amine 1.12 (m,7H), 0.85 (q, J = 11.8, 2H). 69 2-{2-[(9R)-9-(pyridin-2- 363.1 δ 8.77(d, J = 4.0, 1H), 8.09 (td, J = 8.0, 1.7, 1H), yl)-6- 7.64 (d, J = 8.1,1H), 7.55 (dd, J = 7.1, 5.8, 1H), 7.35 (dd, J = 5.6,oxaspiro[4.5]decan-9- 3.2, 2H), 7.24 (d, J = 3.6, 2H), 4.76 (m, 4H),yl]ethyl}-2,3-dihydro- 4.21 (brs, 1H), 3.77 (m, 2H), 3.30 (m, 1H), 2.80(td, J = 12.3, 1H-isoindole 4.4, 1H), 2.49 (td, J = 12.9, 4.5, 1H), 2.38(t, J = 15.1, 2H), 2.23 (td, J = 12.9, 4.2, 1H), 2.07 (d, J = 14.0, 1H),1.87 (ddd, J = 24.1, 11.9, 7.1, 2H), 1.69 (m, 1H), 1.51 (dt, J = 24.2,10.9, 4H), 1.15 (m, 1H), 0.78 (dt, J = 13.4, 9.0, 1H). 70{2-[2,2-diethyl-4-(4- 364.4 δ 11.44 (s, 1H), 7.28 (m, 2H), 7.10 (m, 2H),3.75 (m, fluorophenyl)oxan-4- 2H), 2.88 (m, 5H), 2.27 (m, 3H), 1.97 (td,J = 12.7, yl]ethyl}dipropylamine 3.9, 1H), 1.80 (td, J = 12.6, 4.9, 1H),1.66 (m, 2H), 1.46 (m, 6H), 1.04 (m, 1H), 0.88 (m, 10H), 0.55 (m, 3H).71 (2-phenylethyl)({2- 365.1 δ 8.51 (dd, J = 5.3, 1.3, 1H), 8.04 (td, J= 7.9, 1.7, 1H), [(9R)-9-(pyridin-2-yl)-6- 7.56 (d, J = 8.1, 1H), 7.49(dd, J = 7.1, 5.8, 1H), oxaspiro[4.5]decan-9- 7.25-7.12 (m, 6H),7.10-7.03 (m, 2H), 3.88-3.47 (m, yl]ethyl})amine 3H), 3.01 (d, J = 7.5,2H), 2.85 (t, J = 7.8, 2H), 2.44 (s, 1H), 2.38-2.17 (m, 3H), 2.17-1.99(m, 1H), 1.92 (d, J = 14.1, 1H), 1.84-1.66 (m, 3H), 1.58 (d, J = 5.1,1H), 1.40 (ddd, J = 15.2, 12.1, 8.9, 4H), 1.05 (d, J = 6.5, 1H), 0.65(d, J = 13.4, 1H). 72 (2-phenylethyl)({2-[9- 365.3 δ 8.58 (d, J = 4.8,1H), 8.07 (t, J = 7.9, 1H), 7.61 (s, (pyridin-2-yl)-6- 1H), 7.52 (dd, J= 12.0, 6.3, 1H), 7.27 (m, 3H), oxaspiro[4.5]decan-9- 7.20 (m, 2H), 4.04(d, J = 3.2, 2H), 3.76 (ddd, J = 19.4, yl]ethyl})amine 12.6, 8.9, 2H),3.05 (s, 1H), 2.53 (m, 2H), 2.29 (d, J = 43.6, 5H), 1.96 (d, J = 13.9,1H), 1.80 (m, 2H), 1.68 (s, 1H), 1.50 (ddd, J = 20.5, 13.1, 7.0, 4H),1.17 (s, 1H), 0.75 (m, 1H). 73 benzyl({2-[9-(6- 365.7 δ 9.49 (s, 2H),8.18 (t, J = 7.9, 1H), 7.55 (dd, J = 23.1, methylpyridin-2-yl)-6- 7.8,2H), 7.35 (s, 5H), 5.87 (s, 3H), 4.00 (s, 2H), oxaspiro[4.5]decan-9-3.88-3.66 (m, 2H), 3.00 (s, 1H), 2.80 (s, 3H), 2.65 (d, J = 12.5,yl]ethyl})amine 1H), 2.53 (s, 1H), 2.31 (d, J = 14.3, 2H), 2.20 (d, J =13.5, 1H), 2.11-2.00 (m, 1H), 1.97-1.80 (m, 2H), 1.70 (d, J = 5.3, 1H),1.52 (ddd, J = 29.7, 17.1, 7.4, 4H), 1.28 (t, J = 7.1, 1H), 0.95-0.79(m, 1H). (ddd, J = 29.7, 17.1, 7.4, 4H), 1.28 (t, J = 7.1, 1H),0.92-0.77 (m, 1H). 74 {2-[2,2-dimethyl-4-(4- 366.3 1H NMR (400 MHz324.3,CDCl3) δ 8.50 (d, J = 223.4, methylphenyl)oxan-4- 2H), 7.25 (s, 5H),6.95 (d, 338.3 J = 8.1, 2H), 6.87 (d, J = 8.3, yl]ethyl}(2- 2H), 5.69(s, 3H), 3.62 (dd, J = 6.8, 2.5, 2H), phenylpropan-2- 2.38 (dd, J =15.7, 13.2, 1H), 2.22 (s, 3H), 1.98 (m, yl)amine 2H), 1.80 (m, 2H), 1.63(m, 1H), 1.56 (s, 3H), 1.51 (s, 3H), 1.47 (d, J = 14.1, 1H), 1.39 (dd, J= 10.5, 4.0, 1H), 1.06 (s, 3H), 0.53 (s, 3H). 75 {2-[(9R)-9-(pyridin-2-367.1 δ 8.90 (s, 1H), 8.75 (d, J = 4.4, 1H), 8.61 (d, J = 5.2, yl)-6-1H), 8.41-8.28 (m, 2H), 7.87-7.70 (m, 3H), 3.81 (s,oxaspiro[4.5]decan-9- 1H), 3.71 (s, 1H), 3.29 (t, J = 10.5, 3H), 2.97(d, J = 7.3, yl]ethyl}[2-(pyridin-3- 1H), 2.44 (s, 2H), 2.33 (t, J =11.9, 2H), 2.21 (dt, J = 24.1, yl)ethyl]amine 11.9, 1H), 2.07 (d, J =14.3, 1H), 1.88 (d, J = 10.3, 2H), 1.65 (dd, J = 16.4, 9.9, 1H),1.60-1.44 (m, 5H), 1.19 (s, 1H), 0.81 (d, J = 13.1, 1H). 76[(2-methylpyrimidin-5- 367.1 δ 8.57 (s, 2H), 7.83-7.66 (m, 1H), 7.33 (s,4H), yl)methyl]({2-[(9R)-9- 7.21 (dt, J = 10.8, 2.9, 1H), 3.93 (s, 1H),3.69 (s, 2H), (pyridin-2-yl)-6- 2.65 (s, 1H), 2.40-2.20 (m, 3H), 2.09(s, 2H), 1.87 (s, 2H), oxaspiro[4.5]decan-9- 1.76-1.50 (m, 3H), 1.42(ddd, J = 33.3, 13.0, 3.9, yl]ethyl})amine 2H), 1.22 (td, J = 7.3, 1.9,1H), 1.02 (s, 1H), 0.71-0.54 (m, 1H). 77 {2-[2,2-dimethyl-4-(4- 368.3 δ7.16 (m, 6H), 6.85 (dd, J = 18.0, 7.8, 2H), 3.80 (s,methylphenyl)oxan-4- 3H), 3.61 (d, J = 1.9, 2H), 3.51 (s, 2H), 2.45 (d,J = 5.2, yl]ethyl}[(2- 1H), 2.35 (s, 4H), 2.15 (m, 2H), 1.81 (m, 1H),1.66 (s, methoxyphenyl)methyl]amine 4H), 1.20 (s, 3H), 0.69 (s, 3H). 78{2-[2,2-dimethyl-4-(4- 368.3 δ 9.28 (s, 1H), 8.80 (s, 1H), 7.10 (m, 1H),7.01 (q, J = 8.4, methylphenyl)oxan-4- 4H), 6.74 (dd, J = 8.2, 2.0, 1H),6.65 (dd, J = 15.6, yl]ethyl}[(3- 4.8, 2H), 3.66 (m, 7H), 2.64 (s, 4H),2.24 (s, 3H), methoxyphenyl)methyl]amine 2.09 (m, 3H), 1.82 (m, 1H),1.64 (m, 1H), 1.48 (ddd, J = 13.4, 13.4, 9.8, 8.8, 2H), 1.10 (s, 3H),0.57 (s, 3H). 79 benzyl({2-[9-(4- 368.3 δ 8.82 (d, J = 134.2, 2H), 7.31(m, 3H), 7.16 (m, 4H), fluorophenyl)-6- 7.00 (dd, J = 10.7, 6.5, 2H),3.72 (m, 4H), 2.70 (s, oxaspiro[4.5]decan-9- 1H), 2.28 (s, 1H), 1.92 (m,6H), 1.62 (m, 2H), 1.46 (m, yl]ethyl})amine 4H), 1.23 (m, 1H), 0.77 (dt,J = 13.6, 8.8, 1H) 80 benzyl({2-[(9S)-9-(4- 368.3 δ 9.09 (s, 1H), 8.74(s, 1H), 7.31 (m, 3H), 7.16 (m, fluorophenyl)-6- 4H), 7.00 (t, J = 8.6,2H), 3.73 (m, 4H), 2.67 (s, 1H), oxaspiro[4.5]decan-9- 2.26 (s, 1H),2.02 (s, 2H), 1.94 (td, J = 12.6, 4.7, 1H), yl]ethyl})amine 1.85 (d, J =13.9, 3H), 1.62 (s, 2H), 1.46 (dd, J = 7.8, 4.0, 4H), 1.24 (d, J = 12.7,1H), 0.77 (dt, J = 13.6, 8.7, 1H) 81 benzyl({2-[(9R)-9-(4- 368.3 δ7.24-7.17 (m, 2H), 7.16-7.09 (m, 3H), 7.01 (d, J = 7.8, fluorophenyl)-6-2H), 6.89 (d, J = 8.0, 2H), 3.68 (ddd, J = 11.8, oxaspiro[4.5]decan-9-5.0, 1.3, 1H), 3.62-3.49 (m, 3H), 2.32 (t, J = 7.3, yl]ethyl})amine 2H),2.25 (s, 3H), 2.22-2.13 (m, 1H), 1.93 (dtd, J = 15.7, 7.7, 3.8, 1H),1.81-1.66 (m, 2H), 1.65-1.56 (m, 1H), 1.37 (d, J = 20.2, 1H), 1.20-1.05(m, 2H), 1.01-1.02 (m, 2H), 0.86 (t, J = 12.7, 1H). 82 2-[(9R)-9-(2- 369δ 8.59 (ddd, J = 4.8, 1.9, 0.9, 1H), 7.64 (m, 1H), {4H,5H,6H-thieno[2,3-7.32 (t, J = 5.9, 1H), 7.15 (d, J = 4.9, 1H), 7.12 (ddd, J = 7.5,c]pyrrol-5- 4.8, 1.0, 1H), 6.74 (d, J = 4.9, 1H), 3.80 (m, 4H),yl}ethyl)-6- 3.68 (m, 2H), 2.63 (td, J = 11.6, 5.1, 1H), 2.49 (dd, J =13.8, oxaspiro[4.5]decan-9- 2.2, 1H), 2.37 (dd, J = 13.7, 2.0, 1H), 2.16(td, J = 11.6, yl]pyridine 4.4, 1H), 2.05 (m, 1H), 1.79 (m, 3H), 1.62(d, J = 7.8, 2H), 1.50 (m, 3H), 1.40 (m, 1H), 1.14 (ddd, J = 9.7, 7.6,3.2, 1H), 0.72 (dt, J = 13.4, 8.9, 1H). 83 [(4,5-dimethylfuran-2- 369.1δ 10.28 (brs, 1H), 9.39 (brs, 1H), 8.70 (d, J = 4.6,yl)methyl]({2-[(9R)-9- 1H), 8.12 (t, J = 7.5, 1H), 7.65 (d, J = 8.1,1H), (pyridin-2-yl)-6- 7.58 (m, 1H), 6.14 (s, 1H), 3.91 (q, J = 14.4,2H), 3.75 (m, oxaspiro[4.5]decan-9- 2H), 2.95 (dd, J = 10.9, 5.9, 1H),2.51 (t, J = 9.7, 1H), yl]ethyl})amine 2.33 (m, 3H), 2.10 (s, 3H), 1.99(d, J = 14.1, 1H), 1.82 (m, 5H), 1.68 (m, 1H), 1.48 (m, 4H), 1.15 (m,1H), 0.74 (dt, J = 13.2, 8.9, 1H). 84 {2-[(9R)-9-(4- 369.2 δ 8.53 (s,2H), 7.78 (s, 3H), 7.29-7.05 (m, 6H), fluorophenyl)-6- 6.96 (t, J = 8.4,3H), 4.07 (s, 2H), 3.66 (d, J = 12.5, 2H), oxaspiro[4.5]decan-9- 2.83(s, 1H), 2.37 (s, 1H), 2.11 (d, J = 13.7, 1H), yl]ethyl}(pyridin-4- 2.01(d, J = 13.3, 2H), 1.83 (d, J = 14.0, 2H), 1.49 (t, J = 61.9,ylmethyl)amine 9H), 1.17 (s, 2H), 0.70 (dt, J = 17.4, 8.9, 1H). 852-[({2-[4-(4- 370.3 δ 8.05 (d, J = 152.9, 2H), 7.08 (m, 1H), 7.01 (d, J= 8.9, methoxyphenyl)-2,2- 2H), 6.82 (m, 2H), 6.76 (d, J = 8.8, 2H),6.69 (t, J = 7.3, dimethyloxan-4- 1H), 4.00 (s, 2H), 3.77 (s, 2H), 3.70(s, 3H), yl]ethyl}amino)methyl]phenol 3.65 (dd, J = 6.9, 2.6, 2H), 2.61(s, 1H), 2.23 (s, 1H), 2.04 (dd, J = 23.7, 13.9, 2H), 1.93 (s, 1H), 1.81(td, J = 12.5, 4.9, 1H), 1.60 (td, J = 12.7, 4.8, 1H), 1.48 (d, J =13.9, 2H), 1.08 (s, 3H), 0.55 (s, 3H). 86 benzyl({2-[2,2-diethyl- 370.3δ 7.26-7.14 (m, 3H), 7.13-7.02 (m, 4H), 6.91 (t, J = 8.6, 4-(4- 2H),3.69-3.47 (m, 4H), 2.51 (td, J = 12.2, 4.7, fluorophenyl)oxan-4- 1H),2.14-1.94 (m, 3H), 1.83 (td, J = 12.7, 4.3, 1H), yl]ethyl})amine 1.64(td, J = 12.6, 4.7, 1H), 1.56-1.35 (m, 3H), 1.27 (tt, J = 27.2, 13.7,1H), 0.95 (dq, J = 14.7, 7.4, 1H), 0.84-0.58 (m, 4H), 0.43 (t, J = 7.4,3H). 87 benzyl({2-[4-(4- 370.3 δ 9.15 (s, 2H), 7.32 (m, 3H), 7.25 (m,2H), 7.18 (dd, J = 7.3, fluorophenyl)-2,2,6,6- 2.1, 2H), 6.99 (dd, J =12.0, 5.3, 2H), 3.72 (s, tetramethyloxan-4- 2H), 2.34 (dd, J = 53.2,23.4, 2H), 1.91 (dd, J = 10.4, yl]ethyl})amine 6.5, 2H), 1.68 (d, J =14.3, 2H), 1.27 (s, 6H), 1.02 (s, 6H). 88 [(2,3- 370.3 δ 7.13 (s, 4H),6.95 (m, 1H), 6.80 (dd, J = 8.2, 1.4, dimethoxyphenyl)methyl]({2- 1H),6.72 (dd, J = 7.6, 1.4, 1H), 3.83 (s, 3H), 3.75 (m, [4-(4- 5H), 3.63 (s,2H), 3.54 (ddd, J = 11.6, 9.1, 2.7, 2H), methylphenyl)oxan-4- 2.31 (m,5H), 2.10 (m, 3H), 1.82 (ddd, J = 13.3, 8.3, yl]ethyl})amine 3.7, 4H) 89[(3-methylthiophen-2- 371.1 δ 9.68 (s, 1H), 8.75 (s, 1H), 8.16 (m, 1H),7.74 (d, J = 27.0, yl)methyl]({2-[(9R)-9- 2H), 7.27 (d, J = 1.5, 1H),6.85 (d, J = 5.1, 1H), (pyridin-2-yl)-6- 4.10 (m, 2H), 3.84 (d, J =12.7, 1H), 3.66 (d, J = 10.3, oxaspiro[4.5]decan-9- 1H), 2.96 (m, 1H),2.69 (m, 1H), 2.54 (m, 3H), yl]ethyl})amine 2.35 (m, 4H), 2.11 (d, J =14.0, 1H), 1.87 (d, J = 10.3, 3H), 1.57 (m, 5H), 1.06 (m 1H), 0.78 (d, J= 12.8, 1H). 90 {2-[(9R)-9-(pyridin-2- 371.1 δ 8.80-8.66 (m, 1H),8.45-8.25 (m, 1H), yl)-6- 7.84-7.63 (m, 2H), 7.16 (dd, J = 5.1, 1.1,1H), 6.91 (dd, J = 5.1, oxaspiro[4.5]decan-9- 3.5, 1H), 6.83 (dd, J =3.4, 0.9, 1H), 3.83 (tt, J = 13.7, yl]ethyl}[2-(thiophen- 6.9, 1H), 3.69(dd, J = 20.1, 10.1, 1H), 3.16 (s, 2-yl)ethyl]amine 4H), 3.02 (s, 1H),2.61-2.22 (m, 5H), 2.20-1.98 (m, 1H), 1.98-1.77 (m, 2H), 1.76-1.63 (m,1H), 1.50 (tdd, J = 12.3, 10.9, 5.3, 4H), 1.17 (dd, J = 7.9, 5.2, 1H),0.76 (dt, J = 13.0, 8.8, 1H). 91 [(2-methylthiophen-3- 371.1 δ 8.68 (d,J = 5.4, 1H), 8.26 (s, 1H), 7.82-7.63 (m, yl)methyl]({2-[(9R)-9- 2H),7.05 (t, J = 10.0, 1H), 6.94 (d, J = 5.3, 1H), (pyridin-2-yl)-6- 3.96(s, 2H), 3.82 (s, 1H), 3.72 (s, 1H), 3.03 (s, 1H), oxaspiro[4.5]decan-9-2.50 (d, J = 15.9, 2H), 2.39 (s, 3H), 2.30 (dd, J = 12.6, 7.5,yl]ethyl})amine 3H), 2.02 (d, J = 14.2, 1H), 1.92-1.79 (m, 2H), 1.70(dt, J = 14.5, 10.2, 1H), 1.64-1.38 (m, 4H), 1.25-1.13 (m, 1H), 0.79 (d,J = 13.2, 1H). 92 [(5-methylthiophen-2- 371.2 δ 8.71 (d, J = 4.7, 1H),8.14 (t, J = 7.6, 1H), yl)methyl]({2-[(9R)-9- 7.78-7.48 (m, 2H), 6.86(d, J = 3.4, 1H), 6.78-6.53 (m, (pyridin-2-yl)-6- 1H), 4.09 (s, 2H),3.76 (ddd, J = 40.6, 14.3, 7.2, 2H), oxaspiro[4.5]decan-9- 3.17-2.85 (m,1H), 2.64-2.23 (m, 4H), 2.16 (dd, J = 16.4, yl]ethyl})amine 8.6, 1H),1.99 (d, J = 14.2, 1H), 1.89-1.75 (m, 2H), 1.75-1.61 (m, 1H), 1.61-1.35(m, 4H), 1.24-1.05 (m, 1H), 0.74 (dt, J = 13.2, 8.9, 1H). 93{2-[9-(6-methylpyridin- 371.2 δ 9.47 (d, J = 86.3, 2H), 8.17 (t, J =8.0, 1H), 7.58 (d, 2-yl)-6- J = 8.0, 1H), 7.52 (d, J = 7.8, 1H), 7.39(d, J = 1.9, 1H), oxaspiro[4.5]decan-9- 7.31-7.29 (m, 1H), 7.08 (dd, J =5.0, 1.0, 1H), yl]ethyl}(thiophen-3- 6.43 (s, 3H), 4.11-3.95 (m, 2H),3.91-3.67 (m, 2H), ylmethyl)amine 2.97 (s, 1H), 2.81 (s, 3H), 2.61 (t, J= 12.6, 1H), 2.47 (t, J = 10.1, 1H), 2.43-2.15 (m, 3H), 2.15-1.99 (m,1H), 1.87 (dd, J = 12.2, 6.8, 2H), 1.70 (dt, J = 12.7, 6.2, 1H),1.63-1.40 (m, 4H), 1.28-1.20 (m, 1H), 0.84 (dt, J = 13.3, 9.0, 1H). 94{2-[4-(4-fluorophenyl)- 371.3 δ 7.09 (dd, J = 8.9, 5.1, 2H), 6.93 (dd, J= 11.7, 5.5, 1- 2H), 6.71 (d, J = 2.3, 1H), 5.98 (s, 2H), 3.83 (s, 2H),oxaspiro[5.5]undecan- 3.61 (m, 2H), 2.56 (m, 1H), 2.08 (t, J = 12.1,3H), 4- 1.68 (s, 3H), 1.48 (d, J = 14.6, 2H), 1.40 (d, J = 14.1, 2H),yl]ethyl}(1H-pyrrol-2- 1.29 (m, 3H), 1.05 (m, 3H), 0.58 (s, 1H).ylmethyl)amine 95 {2-[9-(6-methylpyridin- 371.3 δ 9.48 (s, 1H), 8.08 (t,J = 7.9, 1H), 7.48 (d, J = 8.0, 2-yl)-6- 1H), 7.42 (d, J = 7.8, 1H),7.22 (dd, J = 5.1, 0.8, 1H), oxaspiro[4.5]decan-9- 7.04 (d, J = 2.9,1H), 6.88 (dd, J = 5.1, 3.5, 1H), yl]ethyl}(thiophen-2- 5.95 (s, 3H),4.13 (s, 2H), 3.66 (ddd, J = 18.7, 12.8, 9.1, ylmethyl)amine 2H), 2.91(s, 1H), 2.71 (s, 3H), 2.60-2.40 (m, 2H), 2.18 (dd, J = 48.6, 14.1, 3H),1.96 (d, J = 14.2, 1H), 1.88-1.68 (m, 2H), 1.71-1.54 (m, 1H), 1.56-1.31(m, 4H), 1.20-1.05 (m, 1H), 0.83-0.63 (m, 1H). 96 [(4-methylthiophen-2-371.3 δ 9.63 (s, 1H), 8.61 (d, J = 4.1, 1H), 8.08 (t, J = 7.8,yl)methyl]({2-[(9R)-9- 1H), 7.61 (d, J = 8.1, 1H), 7.53 (dd, J = 7.0,5.6, 1H), (pyridin-2-yl)-6- 6.91 (s, 1H), 6.88 (s, 1H), 4.14 (m, 2H),3.75 (dt, J = 19.0, oxaspiro[4.5]decan-9- 11.1, 2H), 3.02 (m, 1H), 2.61(m, 1H), 2.40 (brs, yl]ethyl})amine 1H), 2.27 (m, 4H), 2.19 (d, J = 0.8,3H), 1.95 (d, J = 14.0, 1H), 1.79 (m, 2H), 1.66 (dd, J = 12.1, 5.9, 1H),1.47 (m, 4H), 1.16 (m, 1H), 0.74 (dt, J = 13.1, 8.9, 1H). 97{2-[(9R)-9-(4- 372 δ 7.12 (dd, J = 8.9, 5.2, 2H), 6.94 (t, J = 8.6, 2H),fluorophenyl)-6- 6.10 (d, J = 3.1, 1H), 5.79 (dd, J = 3.1, 0.9, 1H),3.77 (m, oxaspiro[4.5]decan-9- 2H), 3.72-3.49 (m, 2H), 2.63 (s, 1H),2.19 (s, 1H), yl]ethyl}[(5- 2.13-2.08 (m, 3H), 2.06 (s, 1H), 1.98 (dd, J= 13.8, methylfuran-2- 1.3, 1H), 1.89 (td, J = 12.7, 4.5, 1H), 1.80 (dd,J = 13.1, yl)methyl]amine 7.1, 2H), 1.71 (dd, J = 13.2, 6.0, 1H), 1.59(ddd, J = 14.2, 9.4, 5.4, 2H), 1.50-1.28 (m, 4H), 1.25-1.09 (m, 1H),0.71 (dt, J = 13.5, 8.8, 1H). 98 [(4-methyl-1,3-thiazol- 372.1 δ 8.68(dd, J = 5.3, 1.2, 1H), 8.25 (s, 1H), 8.09 (td, J = 8.0,2-yl)methyl]({2-[(9R)-9- 1.7, 1H), 7.63 (d, J = 8.1, 1H), 7.54 (dd, J =7.1, (pyridin-2-yl)-6- 5.7, 1H), 6.94 (d, J = 0.9, 1H), 4.37 (m, 2H),3.76 (m, oxaspiro[4.5]decan-9- 2H), 3.14 (td, J = 11.2, 5.9, 1H), 2.73(td, J = 11.4, yl]ethyl})amine 4.7, 1H), 2.40 (m, 4H), 2.27 (m, 3H),2.00 (m, 1H), 1.83 (ddd, J = 13.8, 9.3, 4.4, 2H), 1.66 (m, 1H), 1.49 (m,4H), 1.19 (m, 1H), 0.78 (dt, J = 13.3, 9.0, 1H). 99[(2-methyl-1,3-thiazol- 372.1 δ 8.71 (d, J = 4.3, 1H), 8.33 (td, J =8.0, 1.5, 1H), 5-yl)methyl]({2-[(9R)-9- 7.77 (m, 2H), 7.69 (s, 1H), 5.53(s, 1H), 4.28 (m, 2H), (pyridin-2-yl)-6- 3.78 (m, 2H), 3.04 (td, J =11.4, 5.4, 1H), 2.73 (s, 3H), oxaspiro[4.5]decan-9- 2.56 (m, 2H), 2.30(t, J = 15.3, 3H), 2.04 (m, 1H), yl]ethyl})amine 1.88 (ddd, J = 19.6,11.5, 7.0, 2H), 1.68 (m, 1H), 1.49 (m, 4H), 1.18 (m, 1H), 0.77 (dt, J =13.1, 9.0, 1H). 100 [(4-methyl-1,3-thiazol- 372.1 δ 13.17 (s, 1H), 9.91(s, 1H), 8.88 (s, 1H), 8.69 (d, J = 4.9, 5-yl)methyl]({2-[(9R)-9- 1H),8.31 (t, J = 7.4, 1H), 7.75 (t, J = 7.9, 2H), (pyridin-2-yl)-6- 4.25 (m,2H), 3.77 (m, 2H), 3.04 (td, J = 11.5, 5.0, oxaspiro[4.5]decan-9- 1H),2.57 (dt, J = 10.7, 7.9, 1H), 2.34 (m, 7H), yl]ethyl})amine 2.02 (m,1H), 1.86 (ddd, J = 26.5, 13.3, 8.2, 2H), 1.66 (dt, J = 13.6, 8.4, 1H),1.50 (m, 4H), 1.15 (dd, J = 13.2, 6.6, 1H), 0.73 (dt, J = 13.0, 8.9,1H). 101 [(2- 372.2 δ 7.21 (m, 1H), 7.07 (m, 5H), 7.02 (d, J = 8.2, 2H),chlorophenyl)methyl]({2- 3.69 (m, 2H), 3.58 (d, J = 1.0, 2H), 2.37 (td,J = 10.9, [2,2-dimethyl-4-(4- 5.3, 1H), 2.22 (m, 4H), 2.07 (ddd, J =14.2, 9.9, 3.8, methylphenyl)oxan-4- 2H), 1.74 (ddd, J = 13.2, 10.5,5.1, 1H), 1.55 (m, 3H), yl]ethyl})amine 1.43 (s, 2H), 1.10 (s, 3H), 0.58(s, 3H). 102 [(3- 372.2 δ 9.27 (d, J = 168.2, 2H), 7.19 (m, 2H), 7.11(m, 2H), chlorophenyl)methyl]({2- 7.04 (d, J = 8.2, 2H), 6.99 (d, J =8.2, 3H), 3.67 (m, [2,2-dimethyl-4-(4- 2H), 3.58 (s, 2H), 2.57 (s, 1H),2.33 (d, J = 12.1, 2H), methylphenyl)oxan-4- 2.23 (s, 3H), 2.07 (m, 3H),1.80 (td, J = 12.5, 4.6, 1H), yl]ethyl})amine 1.62 (m, 1H), 1.47 (m,2H), 1.09 (s, 3H), 0.56 (s, 3H). 103 [(4- 372.2 δ 8.80 (d, J = 192.6,2H), 7.19 (t, J = 4.2, 3H), chlorophenyl)methyl]({2- 7.02 (m, 6H), 4.06(s, 3H), 3.68 (dd, J = 12.4, 10.2, 4H), [2,2-dimethyl-4-(4- 2.62 (s,1H), 2.24 (d, J = 13.6, 3H), 2.11 (ddd, J = 21.2, methylphenyl)oxan-4-15.6, 7.6, 3H), 1.80 (dt, J = 12.3, 6.3, 1H), yl]ethyl})amine 1.64 (m,1H), 1.49 (m, 2H), 1.11 (s, 3H), 0.57 (s, 3H). 104 6-[9-{2-[(thiophen-2-373 1H NMR (400 MHz, CD3CN) δ 8.18 (t, J = 1.7, 1H),ylmethyl)amino]ethyl}- 8.11 (brs, 1H), 7.49 (dd, J = 5.1, 1.1, 1H), 7.34(d, J = 1.7, 6- 2H), 7.18 (d, J = 2.7, 1H), 7.06 (dd, J = 5.1, 3.6,oxaspiro[4.5]decan-9- 1H), 4.24 (s, 2H), 3.67 (m, 2H), 2.95 (m, 1H),yl]pyridin-3-ol 2.73 (brs, 1H), 2.51 (d, J = 4.3, 1H), 2.29 (t, J =11.0, 2H), 2.08 (m, 2H), 1.84 (m, 2H), 1.72 (t, J = 8.5, 1H), 1.62 (dd,J = 14.4, 6.5, 2H), 1.48 (dt, J = 23.5, 7.0, 4H), 1.15 (m, 1H), 0.73(dt, J = 12.7, 8.7, 1H). 105 6-[9-{2-[(thiophen-2- 373 δ 7.52 (d, J =16.2, 1H), 7.29 (d, J = 1.1, 1H), 7.12 (d, ylmethyl)amino]ethyl}- J =2.7, 1H), 6.97 (dd, J = 5.1, 3.6, 1H), 6.51 (d, J = 8.9,6-oxaspiro[4.5]decan- 1H), 6.27 (d, J = 7.2, 1H), 4.16 (s, 2H), 3.71 (s,9-yl]pyridin-2-ol 2H), 2.85 (dd, J = 13.9, 7.6, 1H), 2.68 (dd, J = 18.4,9.5, 1H), 2.31 (m, 2H), 1.94 (d, J = 13.6, 2H), 1.59 (m, 10H), 0.90 (m,1H). 106 [(5-methylthiophen-2- 373.2 δ 8.73 (dd, J = 5.5, 1.4, 2H), 8.24(td, J = 8.0, 1.6, 1H), yl)methyl]({2-[2,2,6,6- 7.87 (d, J = 8.2, 1H),7.69 (dd, J = 7.0, 6.1, 1H), tetramethyl-4-(pyridin- 6.83 (dd, J = 20.2,3.4, 1H), 6.67-6.48 (m, 1H), 4.09 (s, 2-yl)oxan-4- 2H), 2.83-2.69 (m,2H), 2.52 (dd, J = 19.1, 11.7, yl]ethyl})amine 3H), 2.41 (d, J = 0.5,3H), 2.37-2.21 (m, 2H), 1.89 (d, J = 14.8, 2H), 1.31 (s, 6H), 0.98 (s,6H). 107 2-(9-{2-[(thiophen-2- 373.2 δ 9.46 (m, 2H), 7.95 (d, J = 6.6,1H), 7.25 (d, J = 5.1, ylmethyl)amino]ethyl}- 1H), 7.10 (s, 1H), 7.03(t, J = 5.8, 2H), 6.90 (dd, J = 5.1, 6- 3.6, 1H), 4.10 (s, 2H), 3.62 (m,2H), 2.84 (s, 1H), oxaspiro[4.5]decan-9- 2.49 (s, 1H), 2.28 (s, 1H),2.06 (dd, J = 44.3, 14.1, yl)pyridin-4-ol 3H), 1.66 (m, 4H), 1.35 (ddd,J = 72.6, 39.8, 18.9, 6H), 0.68 (s, 1H). 108 [(4-methylthiophen-2- 373.3δ 8.75 (d, J = 4.6, 1H), 8.35 (td, J = 8.1, 1.3, 1H),yl)methyl]({2-[2,2,6,6- 7.96 (d, J = 8.2, 1H), 7.86-7.74 (m, 1H),6.95-6.80 (m, tetramethyl-4-(pyridin- 2H), 4.14 (s, 2H), 2.87-2.68 (m,2H), 2.52 (d, J = 14.8, 2-yl)oxan-4- 2H), 2.45-2.29 (m, 2H), 2.18 (d, J= 0.7, 3H), yl]ethy})amine 1.93 (d, J = 14.9, 2H), 1.31 (s, 6H), 0.98(s, 6H). 109 dibutyl({2-[(9R)-9- 373.4 δ 8.78 (d, J = 4.6, 1H), 8.05 (t,J = 7.5, 1H), 7.62 (d, J = 8.0, (pyridin-2-yl)-6- 1H), 7.50 (m, 1H),3.80 (m, 2H), 3.06 (t, J = 10.5, oxaspiro[4.5]decan-9- 1H), 2.90 (s,4H), 2.42 (m, 4H), 2.02 (m, 2H), yl]ethyl})amine 1.83 (m, 2H), 1.68 (tt,J = 13.3, 6.8, 1H), 1.43 (m, 12H), 1.15 (dd, J = 13.2, 5.7, 1H), 0.91(dt, J = 11.8, 7.1, 6H), 0.72 (dt, J = 13.3, 9.0, 1H). 110{2-[(9R)-9-(4- 374.2 δ 7.33-7.23 (m, 7H), 7.19 (dd, J = 8.9, 5.2, 2H),fluorophenyl)-6- 7.04 (t, J = 8.6, 2H), 6.98 (dd, J = 5.0, 1.3, 1H),3.84 (s, oxaspiro[4.5]decan-9- 2H), 3.79-3.69 (m, 2H), 2.67 (s, 1H),2.19-1.74 (m, yl]ethyl}(thiophen-3- 22H), 1.66 (ddd, J = 14.0, 9.3, 4.6,3H), 1.48 (ddd, J = 23.7, ylmethyl)amine 15.2, 8.6, 4H), 1.28 (s, 1H),0.99-0.64 (m, 1H). 111 {2-[(9R)-9-(4- 374.2 δ 9.04 (d, J = 106.1, 2H),7.21 (dd, J = 5.1, 1.1, 1H), fluorophenyl)-6- 7.10 (m, 2H), 6.92 (m,3H), 6.86 (dd, J = 5.1, 3.6, 1H), oxaspiro[4.5]decan-9- 3.93 (s, 2H),3.64 (m, 3H), 2.63 (d, J = 7.9, 1H), yl]ethyl}(thiophen-2- 2.22 (t, J =9.7, 1H), 2.05 (d, J = 14.1, 1H), 1.97 (d, J = 13.9, ylmethyl)amine 1H),1.88 (td, J = 12.7, 4.6, 1H), 1.75 (m, 3H), 1.57 (m, 2H), 1.38 (m, 3H),1.17 (dd, J = 14.1, 6.1, 1H), 0.70 (dt, J = 13.6, 8.8, 1H). 112(cyclopentylmethyl)({2- 374.3 δ 7.15 (dd, J = 8.9, 5.2, 2H), 6.96 (s,2H), 3.64 (d, J = 13.0, [4-(4-fluorophenyl)-1- 3H), 2.59 (s, 3H), 2.11(m, 3H), 1.94 (dd, J = 10.4, oxaspiro[5.5]undecan- 5.7, 2H), 1.68 (dd, J= 12.4, 4.8, 2H), 1.53 (m, 4-yl]ethyl})amine 8H), 1.31 (d, J = 19.9,4H), 1.03 (s, 7H), 0.65 (m, 1H). 113 {2-[2,2-diethyl-4-(4- 376.2 δ7.20-7.13 (m, 8H), 7.09 (dd, J = 8.9, 5.2, 2H), fluorophenyl)oxan-4-6.93 (t, J = 8.6, 2H), 6.87 (dd, J = 4.9, 1.3, 1H), 3.70 (s,yl]ethyl}(thiophen-3- 2H), 3.61 (d, J = 2.3, 2H), 2.56 (s, 1H), 2.02 (d,J = 14.1, ylmethyl)amine 3H), 1.75 (s, 11H), 1.44 (d, J = 14.2, 5H),0.95 (dd, J = 14.5, 7.4, 1H), 0.73 (t, J = 7.5, 5H), 0.43 (t, J = 7.4,4H). 114 {2-[2,2-diethyl-4-(4- 376.2 δ 7.25-7.15 (m, 3H), 7.15-7.02 (m,4H), 6.91 (t, J = 8.6, fluorophenyl)oxan-4- 2H), 3.82-3.36 (m, 4H), 2.51(td, J = 12.2, 4.7, yl]ethyl}(thiophen-2- 1H), 2.12-1.94 (m, 3H), 1.83(td, J = 12.7, 4.3, 1H), ylmethyl)amine 1.64 (td, J = 12.6, 4.7, 1H),1.55-1.35 (m, 3H), 1.28 (dq, J = 14.7, 7.4, 1H), 0.95 (dq, J = 14.7,7.4, 1H), 0.80-0.64 (m, 4H), 0.43 (t, J = 7.4, 3H). 115{2-[4-(4-fluorophenyl)- 376.2 δ 7.28 (m, 4H), 7.00 (ddd, J = 6.7, 6.3,3.2, 3H), 2,2,6,6- 3.82 (s, 3H), 2.46 (s, 1H), 2.28 (d, J = 14.3, 1H),1.92 (m, tetramethyloxan-4- 1H), 1.57 (m, 2H), 1.69 (d, J = 14.4, 2H),1.28 (s, 6H), yl]ethyl}(thiophen-3- 1.02 (s, 6H). ylmethyl)amine 116{2-[4-(4-fluorophenyl)- 376.2 δ 7.29 (m, 3H), 7.01 (s, 4H), 3.98 (s,2H), 2.50 (m, 2,2,6,6- 2H), 2.30 (d, J = 14.2, 2H), 1.94 (m, 2H), 1.69(d, J = 14.4, tetramethyloxan-4- 2H), 1.28 (s, 6H), 1.03 (s, 6H).yl]ethyl}(thiophen-2- ylmethyl)amine 117 benzyl({2-[9-(2- 380.3 δ 8.86(d, J = 149.6, 2H), 7.25-7.19 (m, 3H), methoxyphenyl)-6- 7.18-7.12 (m,1H), 7.09 (dd, J = 7.4, 2.0, 2H), 6.96 (dd, J = 7.8,oxaspiro[4.5]decan-9- 1.5, 1H), 6.85-6.75 (m, 2H), 3.74-3.63 (m,yl]ethyl})amine 7H), 2.55 (dd, J = 15.6, 7.9, 3H), 2.11 (d, J = 14.8,2H), 1.75-1.46 (m, 5H), 1.46-1.32 (m, 3H), 1.32-1.22 (m, 1H), 1.17 (d, J= 4.1, 1H), 0.74-0.60 (m, 1H). 118 benzyl({2-[9-(6- 381.3 δ 9.43 (s,1H), 9.20 (s, 1H), 7.52 (m, 2H), 7.30 (dd, J = 5.1,methoxypyridin-2-yl)- 1.8, 3H), 7.21 (m, 2H), 6.78 (d, J = 7.3, 1H), 6-6.57 (d, J = 8.1, 1H), 3.83 (s, 3H), 3.77 (s, 2H), oxaspiro[4.5]decan-9-3.71 (dd, J = 7.8, 2.7, 2H), 2.77 (s, 1H), 2.32 (d, J = 13.6,yl]ethyl})amine 2H), 2.25 (d, J = 11.5, 1H), 2.06 (td, J = 11.9, 4.8,1H), 1.76 (m, 3H), 1.59 (m, 3H), 1.47 (m, 3H), 1.38 (m, 1H), 1.15 (m,1H), 0.70 (m, 1H). 119 {2-[2,2-dimethyl-4-(4- 382.3 δ 10.17 (m, 3H),7.41 (tdd, J = 8.3, 4.8, 1.6, 1H), methylphenyl)oxan-4- 7.13 (m, 5H),6.93 (m, 2H), 4.20 (dd, J = 14.9, 5.8, 1H), yl]ethyl}[(2- 3.98 (ddd, J =32.2, 12.9, 4.8, 1H), 3.80 (dd, J = 7.4,methoxyphenyl)methyl]methylamine 2.6, 5H), 2.94 (d, J = 114.3, 1H), 2.35(m, 9H), 2.05 (ddd, J = 17.1, 12.7, 6.5, 1H), 1.89 (dt, J = 12.8, 6.2,1H), 1.67 (ddd, J = 22.2, 14.2, 5.0, 2H), 1.23 (d, J = 10.7, 3H), 0.69(t, J = 9.5, 3H). 120 {2-[9-(4-fluorophenyl)- 382.3 δ 8.90 (d, J =138.8, 2H), 7.15 (tt, J = 13.7, 7.6, 4H), 6-oxaspiro[4.5]decan- 6.97 (m,4H), 3.70 (m, 4H), 2.67 (s, 1H), 2.27 (s, 4H), 9- 2.00 (m, 3H), 1.82 (m,3H), 1.63 (m, 2H), 1.46 (m, yl]ethyl}[(3- 4H), 1.24 (d, J = 9.6, 1H),0.78 (dt, J = 13.6, 8.8, 1H) methylphenyl)methyl]amine 121{2-[(9S)-9-(4- 382.3 δ 8.73 (d, J = 138.2, 2H), 7.16 (m, 4H), 7.00 (dd,J = 10.5, fluorophenyl)-6- 6.7, 2H), 6.94 (m, 2H), 3.72 (m, 4H), 2.69(m, oxaspiro[4.5]decan-9- 1H), 2.27 (s, 4H), 2.05 (m, 2H), 1.94 (td, J =12.6, 4.7, yl]ethyl}[(3- 1H), 1.83 (m, 3H), 1.63 (ddd, J = 14.1, 9.6,4.6, 2H), methylphenyl)methyl]amine 1.47 (m, 4H), 1.23 (m, 1H), 0.78(dt, J = 13.9, 8.9, 1H) 122 {2-[(9R)-9-(4- 382.3 δ 8.96 (d, J = 123.7,2H), 7.15 (m, 4H), 6.98 (m, 4H), fluorophenyl)-6- 3.71 (m, 4H), 2.66 (s,1H), 2.25 (d, J = 14.0, 4H), oxaspiro[4.5]decan-9- 2.05 (m, 2H), 1.94(td, J = 12.7, 4.6, 1H), 1.81 (m, 3H), yl]ethyl}[(3- 1.63 (ddd, J =14.2, 7.7, 3.4, 2H), 1.47 (m, 4H), methylphenyl)methyl]amine 1.23 (m,1H), 0.77 (dt, J = 13.7, 8.9, 1H) 123 benzyl({2-[4-(4- 382.3 δ 7.23 (m,3H), 7.10 (dd, J = 4.6, 2.6, 4H), 6.92 (s, fluorophenyl)-1- 2H), 3.64(s, 2H), 2.63 (m, 1H), 2.07 (t, J = 13.9, 3H), oxaspiro[5.5]undecan-1.74 (s, 2H), 1.48 (d, J = 8.3, 3H), 1.40 (d, J = 14.0,4-yl]ethyl})amine 2H), 1.29 (m, 3H), 1.06 (m, 4H), 0.57 (m, 1H). 124{2-[(9R)-9-(4- 382.3 δ 7.47-7.32 (m, 3H), 7.31-7.22 (m, 2H), 7.11 (dd, J= 8.9, fluorophenyl)-6- 5.2, 2H), 6.98 (t, J = 8.6, 2H), 6.28 (s, 2H),oxaspiro[4.5]decan-9- 4.03 (s, 1H), 3.79-3.58 (m, 2H), 2.51 (s, 1H),2.19 (d, J = 14.5, yl]ethyl}[(1R)-1- 1H), 2.07-1.90 (m, 3H), 1.89-1.71(m, 3H), phenylethyl]amine 1.72-1.32 (m, 9H), 1.32-1.10 (m, 1H), 0.78(dt, J = 13.6, 8.8, 1H). 125 {2-[(9R)-9-(4- 382.3 δ 7.47-7.32 (m, 3H),7.31-7.22 (m, 2H), 7.11 (dd, J = 8.9, fluorophenyl)-6- 5.2, 2H), 6.98(t, J = 8.6, 2H), 6.28 (s, 2H), oxaspiro[4.5]decan-9- 4.03 (s, 1H),3.79-3.58 (m, 2H), 2.51 (s, 1H), 2.19 (d, J = 14.5, yl]ethyl}[(1S)-1-1H), 2.07-1.90 (m, 3H), 1.89-1.71 (m, 3H), phenylethyl]amine 1.72-1.32(m, 9H), 1.32-1.10 (m, 1H), 0.78 (dt, J = 13.6, 8.8, 1H). 126{2-[2,2-dimethyl-4-(4- 383.3 δ 7.94 (dd, J = 8.1, 1.2, 1H), 7.53 (td, J= 7.6, 1.3, methylphenyl)oxan-4- 1H), 7.40 (m, 2H), 7.15 (m, 4H), 3.80(m, 4H), yl]ethyl}[(2- 2.48 (td, J = 10.9, 5.4, 1H), 2.32 (m, 4H), 2.18(ddd, J = 12.7, nitrophenyl)methyl]amine 7.8, 3.7, 2H), 1.84 (ddd, J =13.2, 10.4, 5.1, 1H), 1.63 (m, 4H), 1.21 (s, 3H), 0.69 (s, 3H). 127{2-[2,2-dimethyl-4-(4- 383.3 δ 9.09 (d, J = 219.1, 2H), 8.12 (dd, J =8.2, 1.6, 1H), methylphenyl)oxan-4- 8.01 (s, 1H), 7.45 (dt, J = 15.6,7.7, 2H), 7.03 (q, J = 8.5, yl]ethyl}[(3- 4H), 3.87 (s, 2H), 3.69 (m,2H), 3.42 (s, 1H), nitrophenyl)methyl]amine 3.22 (s, 2H), 2.73 (d, J =4.5, 1H), 2.24 (d, J = 8.2, 4H), 2.12 (m, 2H), 1.85 (m, 1H), 1.69 (dd, J= 12.1, 4.5, 1H), 1.52 (m, 2H), 1.11 (s, 3H), 0.57 (s, 3H). 1282-[({2-[9-(4- 384.2 δ 8.36 (d, J = 129.4, 2H), 7.20 (dd, J = 11.0, 4.6,1H), fluorophenyl)-6- 7.14 (dd, J = 8.9, 5.1, 2H), 7.00 (t, J = 8.6,2H), oxaspiro[4.5]decan-9- 6.92 (m, 2H), 6.79 (t, J = 7.1, 1H), 3.88 (s,2H), 3.68 (m, yl]ethyl}amino)methyl]phenol 2H), 2.67 (m, 1H), 2.29 (m,1H), 1.98 (m, 3H), 1.79 (m, 3H), 1.51 (m, 6H), 1.20 (s, 1H), 0.74 (dt, J= 13.8, 8.9, 1H) 129 {2-[4-(4- 384.3 δ 8.47 (d, J = 196.5, 2H), 7.36(td, J = 8.3, 1.7, 1H), methoxyphenyl)-2,2- 7.12 (dd, J = 9.5, 2.6, 2H),7.08 (dd, J = 7.5, 1.6, 1H), dimethyloxan-4- 6.91 (td, J = 7.5, 0.8,1H), 6.86 (d, J = 8.8, 3H), yl]ethyl}[(2- 5.77 (s, 2H), 3.91 (s, 2H),3.82 (s, 3H), 3.79 (s, 3H), methoxyphenyl)methyl]amine 3.77 (m, 2H),2.76 (s, 1H), 2.33 (s, 1H), 2.16 (m, 2H), 1.96 (d, J = 4.6, 1H), 1.77(d, J = 4.7, 1H), 1.59 (m, 2H), 1.19 (s, 3H), 0.66 (s, 3H). 130[(5-ethylthiophen-2- 385.1 δ 8.73 (d, J = 4.6, 1H), 8.20 (t, J = 7.7,2H), yl)methyl]({2-[(9R)-9- 7.80-7.55 (m, 2H), 6.88 (d, J = 3.4, 1H),6.64 (d, J = 3.4, (pyridin-2- 1H), 4.11 (s, 2H), 3.81 (dd, J = 8.4, 4.3,1H), 3.70 (t, J = 10.0, yl)-6- 1H), 3.00 (d, J = 4.6, 1H), 2.86-2.70 (m,2H), oxaspiro[4.5]decan-9- 2.53 (t, J = 10.1, 1H), 2.45-2.25 (m, 3H),2.18 (t, J = 10.0, yl]ethyl})amine 1H), 2.00 (d, J = 14.2, 1H),1.93-1.75 (m, 2H), 1.68 (dd, J = 9.5, 4.4, 1H), 1.62-1.38 (m, 4H), 1.26(t, J = 7.5, 3H), 1.20-1.07 (m, 1H), 0.75 (dt, J = 12.9, 8.8, 1H). 131[(3,5- 385.1 δ 9.45 (brs, 1H), 8.70 (d, J = 5.0, 1H), 8.26 (t, J = 7.7,dimethylthiophen-2- 1H), 7.75 (d, J = 8.1, 1H), 7.70 (m, 1H), 6.46 (d, J= 0.8, yl)methyl]({2-[(9R)-9- 1H), 4.07 (s, 2H), 3.76 (ddd, J = 44.9,13.9, 7.2, (pyridin-2-yl)-6- 2H), 3.05 (m, 1H), 2.58 (m, 1H), 2.43 (t, J= 10.6, 1H), oxaspiro[4.5]decan-9- 2.36 (d, J = 0.7, 3H), 2.24 (dd, J =31.9, 17.7, 3H), yl]ethyl})amine 2.03 (m, 4H), 1.85 (m, 2H), 1.66 (dd, J= 13.8, 8.8, 1H), 1.48 (m, 4H), 1.15 (d, J = 7.9, 1H), 0.75 (dt, J =13.1, 8.9, 1H). 132 {2-[2,2-diethyl-4-(4- 385.3 δ 8.84 (s, 1H), 8.24 (d,J = 8.2, 1H), 7.53 (d, J = 8.2, fluorophenyl)oxan-4- 1H), 7.17 (m, 3H),6.96 (t, J = 8.6, 2H), 4.08 (d, J = 13.9, yl]ethyl}[(6- 2H), 3.63 (d, J= 10.5, 2H), 2.84 (dd, J = 12.0, methylpyridin-3- 8.2, 1H), 2.68 (s,3H), 2.24 (m, 2H), 2.07 (d, J = 14.1, yl)methyl]amine 1H), 1.96 (m, 1H),1.74 (dd, J = 12.5, 8.6, 1H), 1.57 (m, 1H), 1.48 (d, J = 14.2, 1H), 1.41(m, 1H), 1.28 (dd, J = 14.0, 7.4, 1H), 0.96 (dd, J = 14.5, 7.4, 1H),0.73 (td, J = 7.3, 3.9, 4H), 0.44 (t, J = 7.4, 3H). 133{2-[4-(4-fluorophenyl)- 385.3 δ 8.85 (s, 1H), 8.24 (d, J = 8.2, 1H),7.54 (d, J = 8.3, 2,2,6,6- 2H), 7.24 (dd, J = 8.9, 5.1, 1H), 6.92 (m,2H), 4.12 (s, tetramethyloxan-4- 2H), 2.61 (m, 5H), 2.25 (d, J = 14.3,2H), 1.91 (dd, J = 10.4, yl]ethyl}[(6- 6.2, 2H), 1.65 (d, J = 14.4, 2H),1.19 (d, J = 8.9, methylpyridin-3- 6H), 0.94 (s, 6H). yl)methyl]amine134 [(4,5- 385.3 δ 9.46 (s, 1H), 8.62 (d, J = 4.2, 1H), 8.07 (t, J =7.3, dimethylthiophen-2- 1H), 7.60 (d, J = 8.1, 1H), 7.52 (m, 1H), 6.76(s, 1H), yl)methyl]({2-[(9R)-9- 4.06 (q, J = 13.9, 2H), 3.75 (m, 2H),3.01 (m, 1H), (pyridin-2-yl)-6- 2.57 (s, 1H), 2.29 (m, 7H), 2.19 (m,1H), 2.04 (s, 3H), oxaspiro[4.5]decan-9- 1.95 (d, J = 14.0, 1H), 1.81(m, 2H), 1.67 (d, J = 8.2, yl]ethyl})amine 1H), 1.47 (m, 4H), 1.15 (m,1H), 0.74 (dt, J = 13.1, 8.8, 1H). 135 [(2,4-dimethyl-1,3- 386.1 δ 9.59(s, 1H), 8.68 (dd, J = 5.6, 1.4, 1H), 8.35 (td, J = 8.0,thiazol-5-yl)methyl]({2- 1.6, 1H), 7.80 (dd, J = 12.0, 7.0, 2H), 4.22(m, [(9R)-9- 2H), 3.83 (dt, J = 12.5, 4.4, 1H), 3.72 (m, 1H),(pyridin-2-yl)-6- 3.05 (dt, J = 11.2, 5.6, 1H), 2.73 (s, 3H), 2.57 (m,2H), oxaspiro[4.5]decan-9- 2.31 (m, 6H), 2.04 (m, 1H), 1.88 (ddd, J =19.2, 11.4, 6.9, yl]ethyl})amine 2H), 1.68 (m, 1H), 1.52 (m, 4H), 1.19(dd, J = 12.2, 5.9, 1H), 0.76 (dt, J = 13.1, 8.9, 1H). 136{2-[9-(pyrazin-2-yl)-6- 386.1 δ 8.90 (s, 1H), 8.55 (s, 1H), 8.40 (s,1H), 6.60 (s, 1H), oxaspiro[4.5]decan-9- 3.88 (d, J = 12.3, 2H),3.79-3.66 (m, 1H), 3.58 (dd, J = 16.8, yl]ethyl}(thiophen-2- 6.5, 1H),2.81 (s, 1H), 2.40 (s, 1H), ylmethyl)amine 2.35-2.22 (m, 2H), 2.16 (s,3H), 2.12-2.00 (m, 1H), 1.97-1.88 (m, 4H), 1.85 (t, J = 9.1, 1H),1.75-1.49 (m, 3H), 1.49-1.27 (m, 4H), 0.98 (d, J = 11.4, 1H), 0.55 (dt,J = 13.3, 9.0, 1H). 137 [(4,5-dimethylfuran-2- 386.1 δ 9.14 (s, 1H),8.85 (s, 1H), 7.24 (ddd, J = 11.5, 6.2, yl)methyl]({2-[(9R)-9- 3.3, 2H),7.05 (s, 2H), 6.06 (s, 1H), 3.89-3.66 (m, (4- 4H), 2.72 (s, 1H), 2.29(s, 1H), 2.22-2.13 (m, 1H), fluorophenyl)-6- 2.11 (s, 4H), 1.85 (s, 7H),1.76-1.62 (m, 2H), oxaspiro[4.5]decan-9- 1.60-1.36 (m, 4H), 1.33-1.24(m, 1H), 0.82 (dt, J = 13.6, yl]ethyl})amine 8.8, 1H). 138 {2-[9-(2-386.2 δ 8.90 (d, J = 150.1, 2H), 7.19 (dd, J = 3.7, 1.4, 1H),methoxyphenyl)-6- 7.18-7.14 (m, 1H), 6.99 (dd, J = 7.8, 1.5, 1H),oxaspiro[4.5]decan-9- 6.94-6.76 (m, 4H), 4.66 (s, 2H), 3.94 (s, 2H),yl]ethyl}(thiophen-2- 3.80-3.63 (m, 5H), 2.73-2.45 (m, 3H), 2.30-2.08(m, 2H), ylmethyl)amine 1.76-1.48 (m, 5H), 1.39 (dt, J = 7.0, 6.3, 3H),1.30 (d, J = 5.2, 1H), 1.18 (d, J = 4.1, 1H), 0.68 (dd, J = 8.7, 5.0,1H). 139 {2-[9-(2- 386.2 δ 9.28 (d, J = 95.5, 2H), 7.18-7.12 (m, 3H),methoxyphenyl)-6- 6.97 (dd, J = 7.8, 1.5, 1H), 6.93-6.86 (m, 1H),oxaspiro[4.5]decan-9- 6.86-6.71 (m, 2H), 3.80-3.61 (m, 7H), 2.55 (dd, J= 19.5, 5.1, yl]ethyl}(thiophen-3- 3H), 2.12 (d, J = 12.8, 2H), 1.85 (s,2H), ylmethyl)amine 1.76-1.47 (m, 5H), 1.46-1.32 (m, 3H), 1.31-1.22 (m,1H), 1.17 (d, J = 4.2, 1H), 0.74-0.60 (m, 1H). 140 [(3-methoxythiophen-387 δ 11.70 (brs, 1H), 9.14 (d, J = 66.6, 2H), 8.72 (d, J = 4.3,2-yl)methyl]({2-[(9R)-9- 1H), 8.19 (td, J = 8.0, 1.4, 1H), 7.70 (d, J =8.1, (pyridin-2-yl)-6- 1H), 7.63 (dd, J = 7.0, 5.8, 1H), 7.22 (d, J =5.5, 1H), oxaspiro[4.5]decan-9- 6.78 (d, J = 5.6, 1H), 4.08 (m, 2H),3.80 (m, 4H), yl]ethyl})amine 3.69 (dd, J = 11.2, 8.7, 1H), 2.99 (d, J =4.8, 1H), 2.51 (t, J = 9.9, 1H), 2.35 (m, 3H), 2.18 (td, J = 13.5, 5.4,1H), 1.99 (d, J = 14.2, 1H), 1.82 (m, 2H), 1.65 (m, 1H), 1.47 (m, 4H),1.14 (m, 1H), 0.73 (dt, J = 13.2, 8.9, 1H). 141 [(3-methoxythiophen- 387δ 9.03 (d, J = 80.0, 2H), 8.75 (d, J = 5.3, 1H), 8.31 (t,2-yl)methyl]({2-[9- J = 7.9, 1H), 7.76 (m, 2H), 7.26 (t, J = 4.0, 1H),(pyridin-2-yl)-6- 6.81 (d, J = 5.6, 1H), 4.12 (s, 2H), 3.82 (s, 4H),3.69 (dd, J = 24.9, oxaspiro[4.5]decan-9- 14.9, 1H), 3.04 (s, 1H), 2.56(s, 1H), 2.45 (dd, J = 17.7, yl]ethyl})amine 7.6, 1H), 2.29 (ddd, J =17.8, 13.5, 5.8, 3H), 2.05 (d, J = 14.3, 1H), 1.87 (dt, J = 14.4, 6.7,2H), 1.67 (ddd, J = 27.6, 16.0, 6.9, 1H), 1.52 (m, 4H), 1.20 (m, 1H),0.78 (dt, J = 13.0, 8.9, 1H). 142 {2-[9-(6- 387.2 δ 9.37 (s, 1H), 9.11(s, 0H), 7.55 (dd, J = 8.2, 7.5, methoxypyridin-2-yl)- 1H), 7.30 (dd, J= 5.1, 1.1, 1H), 7.03 (d, J = 2.6, 1H), 6-oxaspiro[4.5]decan- 6.96 (dd,J = 5.1, 3.6, 1H), 6.81 (d, J = 7.3, 1H), 9- 6.60 (d, J = 8.0, 1H), 4.07(s, 2H), 3.86 (s, 3H), 3.73 (dd, J = 7.7, yl]ethyl}(thiophen-2- 2.7,2H), 2.87 (m, 1H), 2.75 (brs, 1H), 2.47 (m, ylmethyl)amine 1H), 2.32(dd, J = 24.5, 13.6, 2H), 2.09 (m, 1H), 1.80 (m, 3H), 1.63 (dt, J =15.1, 7.4, 2H), 1.49 (m, 3H), 1.39 (d, J = 4.5, 1H), 1.16 (m, 1H), 0.72(dt, J = 13.4, 8.8, 1H). 143 {2-[9-(6- 387.2 δ 9.40 (s, 1H), 9.21 (s,1H), 7.53 (m, 1H), 7.28 (d, J = 3.0, methoxypyridin-2-yl)- 2H), 6.99(dd, J = 4.8, 1.4, 1H), 6.80 (d, J = 7.4, 6-oxaspiro[4.5]decan- 1H),6.59 (d, J = 8.2, 1H), 3.86 (d, J = 6.4, 5H), 9- 3.72 (dd, J = 7.7, 2.7,2H), 2.78 (m, 1H), 2.30 (dd, J = 28.1, yl]ethyl}(thiophen-3- 12.5, 3H),2.09 (m, 1H), 2.02 (brs, 1H), 1.79 (m, 3H), ylmethyl)amine 1.61 (m, 2H),1.47 (m, 4H), 1.16 (m, 1H), 0.71 (dt, J = 13.4, 8.7, 1H). 144{2-[4-(4-chlorophenyl)- 388.2 δ 8.48 (d, J = 152.7, 2H), 7.28 (td, J =8.3, 1.7, 1H), 2,2-dimethyloxan-4- 7.22 (dd, J = 6.6, 4.8, 2H), 7.06 (m,2H), 6.97 (dd, J = 7.5, yl]ethyl}[(2- 1.6, 1H), 6.81 (ddd, J = 19.8,13.2, 4.6, 2H), methoxyphenyl)methyl]amine 6.03 (s, 1H), 3.82 (s, 2H),3.66 (m, 5H), 2.64 (s, 1H), 2.15 (s, 1H), 2.05 (ddd, J = 22.5, 14.1,2.1, 2H), 1.85 (m, 1H), 1.72 (dd, J = 12.5, 4.7, 1H), 1.53 (m, 2H), 1.11(s, 3H), 0.57 (s, 3H). 145 {2-[(9R)-9-(4- 388.2 δ 7.28 (s, 4H),7.25-7.15 (m, 2H), 7.04 (t, J = 8.6, fluorophenyl)-6- 2H), 6.77 (d, J =3.5, 1H), 6.59 (dd, J = 3.4, 1.1, 1H), oxaspiro[4.5]decan-9- 3.91 (s,2H), 3.85-3.64 (m, 2H), 2.73 (t, J = 9.7, 1H), yl]ethyl}[(5- 2.41 (d, J= 0.7, 3H), 2.37-1.75 (m, 18H), 1.67 (dd, J = 11.7, methylthiophen-2-7.1, 2H), 1.59-1.34 (m, 4H), 1.26 (s, 1H), yl)methyl]amine 0.81 (dt, J =14.0, 8.9, 1H). 146 {2-[4-(4-fluorophenyl)- 388.2 δ 7.18 (s, 1H), 7.15(s, 1H), 7.10 (dd, J = 8.9, 5.2, 2H), 1- 6.92 (dd, J = 10.8, 6.4, 2H),6.87 (m, 1H), 3.67 (d, J = 35.8, oxaspiro[5.5]undecan- 3H), 2.66 (m,1H), 2.07 (s, 3H), 1.83 (m, 2H), 4- 1.56 (s, 3H), 1.41 (d, J = 13.9,2H), 1.33 (m, 3H), yl]ethyl}(thiophen-3- 1.02 (m, 4H), 0.58 (m, 1H).ylmethyl)amine 147 {2-[(9R)-9-(4- 388.2 δ 9.01 (d, J = 137.9, 2H),7.15-7.02 (m, 3H), 6.94 (t, fluorophenyl)-6- J = 8.6, 2H), 6.77-6.63 (m,1H), 4.82 (s, 1H), 3.83 (d, oxaspiro[4.5]decan-9- J = 19.1, 2H),3.73-3.54 (m, 2H), 2.64 (s, 1H), yl]ethyl}[(3- 2.18 (d, J = 10.4, 1H),2.12-1.64 (m, 9H), 1.65-1.50 (m, methylthiophen-2- 2H), 1.50-1.27 (m,4H), 1.27-1.08 (m, 1H), yl)methyl]amine 0.69 (dt, J = 13.5, 8.8, 1H).148 {2-[(9R)-9-(4- 388.2 δ 9.31 (d, J = 89.1, 2H), 7.15-7.05 (m, 2H),6.93 (t, fluorophenyl)-6- J = 8.6, 2H), 6.80-6.65 (m, 2H), 3.80 (s, 2H),oxaspiro[4.5]decan-9- 3.73-3.57 (m, 2H), 2.93 (s, 1H), 2.60 (s, 1H),2.17 (s, 1H), yl]ethyl}[(4- 2.04 (dd, J = 16.0, 3.3, 4H), 1.91 (ddd, J =17.5, 16.7, methylthiophen-2- 9.1, 2H), 1.84-1.65 (m, 3H), 1.57 (ddd, J= 13.2, 9.0, yl)methyl]amine 4.4, 2H), 1.50-1.25 (m, 4H), 1.17 (dd, J =14.9, 5.0, 1H), 0.70 (dt, J = 13.6, 8.8, 1H). 149{2-[4-(4-fluorophenyl)- 388.3 δ 7.28 (s, 3H), 7.22 (dd, J = 8.6, 4.9,2H), 7.01 (m, 1- 2H), 4.01 (s, 2H), 3.74 (s, 1H), 2.26 (m, 1H),oxaspiro[5.5]undecan- 1.73 (m, 11H), 1.52 (d, J = 14.1, 2H), 1.39 (m,2H), 1.13 (s, 4- 2H), 0.69 (m, 1H). yl]ethyl}(thiophen-2- ylmethyl)amine150 {2-[(9R)-9-(4- 389 δ 7.22 (dd, J = 8.9, 5.2, 2H), 7.02 (dd, J =14.0, 5.4, fluorophenyl)-6- 2H), 6.92 (d, J = 0.9, 1H), 4.25 (q, J =14.7, 2H), oxaspiro[4.5]decan-9- 3.73 (m, 2H), 2.89 (td, J = 11.8, 4.8,1H), 2.50 (td, J = 11.7, yl]ethyl}[(4-methyl-1,3- 5.0, 1H), 2.38 (d, J =0.8, 3H), 2.15 (m, 1H), 2.08 (m, thiazol-2- 2H), 1.98 (m, 1H), 1.91 (d,J = 13.9, 1H), 1.79 (d, J = 9.3, yl)methyl]amine 1H), 1.69 (m, 2H), 1.48(m, 5H), 1.25 (m, 1H), 0.81 (dt, J = 13.3, 8.7, 1H). 151{2-[2,2-diethyl-4-(4- 390.2 δ 7.15-7.02 (m, 2H), 6.94 (t, J = 8.6, 2H),6.67 (d, J = 3.5, fluorophenyl)oxan-4- 1H), 6.49 (s, 1H), 3.78 (s, 2H),3.62 (dd, J = 10.4, yl]ethyl}[(5- 8.1, 3H), 2.61 (s, 1H), 2.30 (s, 4H),2.08 (dd, J = 31.6, methylthiophen-2- 14.0, 4H), 1.88 (d, J = 4.6, 1H),1.79-1.34 (m, yl)methyl]amine 19H), 1.29 (dd, J = 14.0, 7.4, 2H), 0.96(dd, J = 14.5, 7.3, 1H), 0.74 (t, J = 7.5, 5H), 0.44 (t, J = 7.4, 4H).152 [(5-chlorothiophen-2- 391 δ 8.75 (d, J = 4.8, 1H), 8.24 (t, J = 7.7,1H), yl)methyl]({2-[(9R)-9- 7.86-7.58 (m, 2H), 6.44 (d, J = 3.3, 1H),6.28 (d, J = 3.3, (pyridin-2-yl)-6- 1H), 4.07 (s, 2H), 3.94-3.79 (m,1H), 3.72 (t, J = 10.1, oxaspiro[4.5]decan-9- 1H), 3.01 (dd, J = 11.1,6.0, 1H), 2.56 (t, J = 9.9, yl]ethyl})amine 1H), 2.49-2.11 (m, 4H), 2.05(d, J = 14.1, 1H), 1.88 (ddd, J = 18.8, 11.0, 6.5, 2H), 1.78-1.31 (m,5H), 1.31-1.07 (m, 1H), 0.77 (dt, J = 13.1, 8.9, 1H) 153dibutyl({2-[4-(4- 392.4 δ 7.37 (m, 2H), 7.07 (m, 2H), 2.83 (dd, J =16.3, 9.4, fluorophenyl)-2,2,6,6- 4H), 2.68 (m, 2H), 2.38 (d, J = 14.3,2H), 2.09 (s, 4H), tetramethyloxan-4- 1.93 (m, 2H), 1.77 (d, J = 14.3,2H), 1.33 (m, 10H), yl]ethyl})amine 1.05 (d, J = 8.6, 6H), 0.91 (t, J =7.2, 6H). 154 {2-[(9R)-9-(4- 396.3 δ 7.37 (s, 5H), 7.28 (s, 0H),7.17-6.99 (m, 3H), fluorophenyl)-6- 6.93 (t, J = 8.6, 2H), 3.81-3.57 (m,2H), 2.45 (d, J = 9.0, oxaspiro[4.5]decan-9- 1H), 2.04-1.72 (m, 7H),1.66 (t, J = 10.7, 6H), yl]ethyl}(2- 1.62-1.53 (m, 2H), 1.52-1.34 (m,4H), 1.23 (s, 1H), phenylpropan-2- 0.78 (d, J = 13.8, 1H). yl)amine 155{4H,5H,6H- 397.1 δ 9.57 (brs, 1H), 8.62 (d, J = 3.9, 1H), 8.02 (t, J =7.1, cyclopenta[b]thiophen- 1H), 7.57 (d, J = 8.1, 1H), 7.48 (dd, J =6.9, 5.5, 1H), 2-ylmethyl}({2- 6.80 (s, 1H), 5.30 (brs, 1H), 4.06 (q, J= 14.1, 2H), [(9R)-9-(pyridin-2-yl)-6- 3.74 (m, 2H), 2.99 (m, 1H), 2.82(t, J = 7.2, 2H), oxaspiro[4.5]decan-9- 2.65 (t, J = 7.2, 2H), 2.57 (m,1H), 2.34 (ddd, J = 33.3, yl]ethyl})amine 21.0, 10.4, 5H), 2.16 (dd, J =9.9, 5.6, 1H), 1.94 (d, J = 13.9, 1H), 1.78 (m, 2H), 1.66 (d, J = 8.0,1H), 1.46 (ddd, J = 16.6, 12.7, 5.7, 4H), 1.14 (m, 1H), 0.72 (dt, J =13.4, 9.0, 1H). 156 {2-[4-(4-fluorophenyl)- 397.3 δ 8.22 (d, J = 8.0,1H), 7.49 (t, J = 16.4, 1H), 7.17 (m, 1- 8H), 6.96 (t, J = 8.6, 2H),4.09 (s, 2H), 3.66 (s, 4H), oxaspiro[5.5]undecan- 2.84 (s, 1H), 2.68 (s,3H), 2.29 (s, 1H), 2.20 (d, J = 13.2, 4- 1H), 2.10 (d, J = 14.1, 1H),1.93 (s, 1H), 1.73 (s, yl]ethyl}[(6- 1H), 1.59 (m, 1H), 1.45 (d, J =14.0, 3H), 1.30 (m, methylpyridin-3- 2H), 1.10 (m, 3H), 0.62 (d, J =11.1, 1H). yl)methyl]amine 157 [(2,3- 398.3 δ 7.05 (dd, J = 19.6, 8.3,4H), 6.88 (m, 1H), 6.74 (dd, dimethoxyphenyl)methyl]({2- J = 8.2, 1.4,1H), 6.62 (dd, J = 7.6, 1.4, 1H), 3.77 (s, [2,2-dimethyl- 3H), 3.68 (m,5H), 3.55 (d, J = 2.3, 2H), 2.37 (m, 1H), 4- 2.22 (m, 4H), 2.06 (ddd, J= 13.8, 8.6, 4.1, 2H), (4-methylphenyl)oxan- 1.73 (dd, J = 6.6, 4.3,1H), 1.56 (m, 4H), 1.10 (s, 3H), 4-yl]ethyl})amine 0.58 (s, 3H). 158[(2,4- 398.3 δ 8.09 (s, 1H), 7.68 (d, J = 33.5, 1H), 7.55 (s, 1H),dimethoxyphenyl)methyl]({2- 7.02 (q, J = 8.4, 4H), 6.86 (m, 1H), 6.32(dd, J = 6.6, [2,2-dimethyl- 2.2, 2H), 3.77 (d, J = 10.4, 2H), 3.69 (m,8H), 2.67 (s, 4- 1H), 2.24 (s, 4H), 2.10 (m, 2H), 1.87 (d, J = 4.5, 1H),(4-methylphenyl)oxan- 1.67 (d, J = 4.4, 1H), 1.51 (m, 2H), 1.10 (s, 3H),4-yl]ethyl})amine 0.57 (s, 3H). 159 {2-[9-(4-fluorophenyl)- 398.3 δ 9.06(d, J = 131.9, 2H), 7.17 (m, 2H), 7.08 (d, J = 8.7,6-oxaspiro[4.5]decan- 2H), 7.00 (t, J = 8.6, 2H), 6.79 (d, J = 8.7, 2H),9-yl]ethyl}[(4- 3.69 (m, 7H), 2.62 (s, 1H), 2.20 (s, 1H), 1.99 (m, 3H),methoxyphenyl)methyl]amine 1.81 (m, 3H), 1.62 (m, 2H), 1.46 (m, 4H),1.24 (d, J = 9.5, 1H), 0.77 (dt, J = 13.4, 8.8, 1H) 160[(5-propylthiophen-2- 399.1 δ 9.43 (s, 2H), 8.72 (d, J = 4.6, 1H), 8.21(t, J = 7.3, yl)methyl]({2-[(9R)-9- 1H), 7.72 (d, J = 8.1, 2H), 6.88 (d,J = 3.5, 1H), (pyridin-2-yl)-6- 6.63 (d, J = 3.5, 1H), 4.11 (s, 2H),3.87-3.65 (m, 2H), oxaspiro[4.5]decan-9- 3.00 (s, 1H), 2.71 (t, J = 7.5,2H), 2.54 (s, 1H), 2.32 (s, 3H), yl]ethyl})amine 2.27-2.11 (m, 1H), 2.02(s, 1H), 1.84 (dd, J = 16.6, 7.3, 2H), 1.64 (dd, J = 15.0, 7.4, 7H),1.22-1.10 (m, 1H), 0.95 (t, J = 7.3, 3H), 0.83-0.72 (m, 1H). 1611-{5-[({2-[(9R)-9- 401.1 δ 9.38 (s, 2H), 8.76 (d, J = 4.6, 1H), 8.29 (t,J = 7.9, (pyridin-2-yl)-6- 1H), 7.84-7.69 (m, 2H), 6.92-6.74 (m, 4H),oxaspiro[4.5]decan-9- 5.02 (d, J = 6.4, 1H), 4.13 (s, 2H), 3.87-3.60 (m,2H), yl]ethyl}amino)methyl]thiophen- 3.03 (s, 1H), 2.52 (s, 1H), 2.34(t, J = 15.7, 3H), 2.20 (t, J = 12.6, 2-yl}ethan-1- 1H), 2.03 (dd, J =14.2, 4.7, 1H), 1.96-1.78 (m, ol 2H), 1.81-1.65 (m, 1H), 1.65-1.43 (m,7H), 1.15 (s, 1H), 0.77 (s, 1H). 162 6-[9-(2-{[(4,5- 401.1 1H NMR (400MHz, CD3CN) δ 8.18 (dd, J = 2.3, 1.2, dimethylthiophen-2- 1H), 7.72 (s,1H), 7.32 (d, J = 2.3, 2H), 6.82 (s, 1H), yl)methyl]amino}ethyl)- 4.10(s, 2H), 3.67 (m, 2H), 2.95 (m, 1H), 2.50 (m, 1H), 6-oxaspiro[4.5]decan-2.32 (s, 3H), 2.27 (d, J = 13.9, 2H), 2.09 (m, 4H), 9- 2.03 (m, 1H),1.88 (m, 1H), 1.83 (t, J = 9.2, 2H), 1.71 (m, yl]pyridin-3-ol 1H), 1.63(m, 2H), 1.48 (ddd, J = 16.6, 12.3, 7.6, 4H), 1.13 (dd, J = 11.7, 5.4,1H), 0.72 (dt, J = 13.7, 9.0, 1H). 163 6-[9-(2-{[(4,5- 401.1 δ 7.49 (m,1H), 6.76 (s, 1H), 6.51 (d, J = 8.9, 1H), dimethylthiophen-2- 6.25 (d, J= 7.0, 1H), 3.99 (s, 2H), 3.71 (m, 2H), yl)methyl]amino}ethyl)- 2.83(dd, J = 16.5, 11.3, 1H), 2.61 (dd, J = 17.0, 5.8, 1H),6-oxaspiro[4.5]decan- 2.27 (d, J = 21.1, 5H), 1.99 (m, 6H), 1.65 (m,10H), 9- 0.98 (dd, J = 18.1, 5.5, 1H). yl]pyridin-2-ol 1642-[9-(2-{[(4,5- 401.2 δ 9.21 (d, J = 64.7, 2H), 8.00 (s, 1H), 7.07 (m,2H), dimethylthiophen-2- 6.67 (s, 1H), 3.95 (s, 2H), 3.62 (m, 2H), 2.84(s, 1H), yl)methyl]amino}ethyl)- 2.44 (s, 1H), 2.27 (d, J = 12.2, 1H),2.16 (s, 4H), 6-oxaspiro[4.5]decan- 2.03 (d, J = 13.5, 2H), 1.94 (s,3H), 1.83 (d, J = 13.9, 1H), 9- 1.65 (m, 3H), 1.37 (m, 5H), 0.75 (s,1H). yl]pyridin-4-ol 165 [(5-nitrothiophen-2- 402 δ 8.59 (d, J = 4.0,1H), 8.15 (t, J = 7.0, 1H), 7.79 (d, J = 4.1, yl)methyl]({2-[(9R)-9-1H), 7.66 (d, J = 8.2, 1H), 7.60 (m, 1H), 7.16 (d, (pyridin-2- J = 4.2,1H), 4.23 (s, 2H), 3.78 (m, 2H), 3.04 (d, J = 6.0, yl)-6- 1H), 2.65 (m,1H), 2.43 (d, J = 9.8, 1H), 2.29 (m, oxaspiro[4.5]decan-9- 3H), 1.98 (d,J = 14.1, 1H), 1.83 (d, J = 5.4, 2H), yl]ethyl})amine 1.67 (m, 1H), 1.48(m, 4H), 1.16 (m, 1H), 0.75 (d, J = 13.2, 1H). 166 [(3,5- 402.1 δ 7.19(dd, J = 8.9, 5.1, 2H), 7.01 (dd, J = 13.7, 5.0, dimethylthiophen-2-2H), 6.43 (s, 1H), 3.87 (m, 2H), 3.72 (m, 2H), 3.02 (s,yl)methyl]({2-[(9R)-9- 1H), 2.72 (dd, J = 14.6, 8.9, 1H), 2.31 (dd, J =31.1, (4- 10.4, 4H), 2.15 (d, J = 13.8, 1H), 2.05 (d, J = 14.0,fluorophenyl)-6- 1H), 1.98 (m, 4H), 1.87 (m, 2H), 1.77 (d, J = 9.7, 1H),oxaspiro[4.5]decan-9- 1.67 (ddd, J = 15.6, 10.3, 5.4, 2H), 1.46 (m, 4H),yl]ethyl})amine 1.25 (t, J = 7.1, 1H), 0.79 (dt, J = 13.7, 8.9, 1H). 167[(5-ethylthiophen-2- 402.1 δ 7.21 (dd, J = 8.9, 5.2, 2H), 7.04 (t, J =8.6, 2H), yl)methyl]({2-[(9R)-9- 6.79 (d, J = 3.5, 1H), 6.62 (d, J =3.5, 1H), 3.92 (s, 2H), (4- 3.80-3.67 (m, 3H), 2.82-2.67 (m, 2H), 2.32(s, 1H), fluorophenyl)-6- 2.16 (d, J = 14.3, 1H), 2.06 (s, 1H), 2.00(td, J = 12.8, 4.9, oxaspiro[4.5]decan-9- 1H), 1.91 (d, J = 13.9, 2H),1.84-1.75 (m, 1H), yl]ethyl})amine 1.69 (s, 2H), 1.50 (d, J = 3.7, 4H),1.25 (t, J = 7.5, 4H), 0.81 (dt, J = 13.4, 8.7, 1H). 168{2-[4-(4-fluorophenyl)- 402.3 δ 7.12 (m, 2H), 6.93 (s, 2H), 6.66 (d, J =3.4, 1H), 1- 6.49 (d, J = 2.5, 1H), 3.80 (s, 2H), 3.63 (s, 2H), 2.65 (m,oxaspiro[5.5]undecan- 1H), 2.31 (s, 3H), 2.12 (m, 2H), 1.85 (m, 1H),1.61 (s, 4-yl]ethyl}[(5- 3H), 1.43 (d, J = 14.0, 2H), 1.33 (m, 3H), 1.03(s, 4H), methylthiophen-2- 0.59 (m, 1H). yl)methyl]amine 169 [(4,5-402.3 δ 8.92 (d, J = 108.6, 2H), 7.15-7.05 (m, 2H), 6.93 (t,dimethylthiophen-2- J = 8.6, 2H), 6.51 (s, 1H), 5.31 (s, 1H), 3.75 (s,2H), yl)methyl]({2-[(9R)-9- 3.69-3.54 (m, 2H), 2.63 (s, 1H), 2.27-2.10(m, 4H), (4- 2.06 (d, J = 14.0, 1H), 1.98 (d, J = 13.9, 1H),fluorophenyl)-6- 1.93-1.84 (m, 4H), 1.84-1.65 (m, 3H), 1.58 (ddd, J =17.0, oxaspiro[4.5]decan-9- 8.4, 3.8, 2H), 1.51-1.27 (m, 4H), 1.17 (dd,J = 13.9, yl]ethyl})amine 6.2, 1H), 0.71 (dt, J = 13.6, 8.8, 1H). 170{[5- 403 δ 9.54 (s, 1H), 8.71 (d, J = 4.5, 1H), 8.26 (t, J = 7.2,(methylsulfanyl)thiophen- 2H), 7.80-7.67 (m, 2H), 6.92 (dd, J = 21.5,3.6, 2H), 2-yl]methyl}({2- 4.15 (s, 2H), 3.76 (d, J = 40.3, 2H), 3.02(td, J = 11.4, [(9R)-9- 5.3, 1H), 2.62-2.51 (m, 1H), 2.48 (s, 3H), 2.42(s, (pyridin-2-yl)-6- 1H), 2.31 (t, J = 13.3, 3H), 2.03 (d, J = 14.2,1H), oxaspiro[4.5]decan-9- 1.92-1.78 (m, 2H), 1.78-1.63 (m, 1H),1.64-1.36 (m, yl]ethyl})amine 4H), 1.25-1.12 (m, 1H), 0.79 (s, 1H). 1716-[9-(2-{[(3- 403 1H NMR (400 MHz, CD3CN) δ 8.15 (d, J = 1.5, 1H),methoxythiophen-2- 7.60 (s, 1H), 7.43 (d, J = 5.6, 1H), 7.31 (m, 2H),yl)methyl]amino}ethyl)- 6.97 (d, J = 5.6, 1H), 4.11 (s, 2H), 3.86 (s,3H), 3.66 (dd, J = 7.8, 6-oxaspiro[4.5]decan- 2.9, 2H), 2.97 (m, 1H),2.51 (m, 1H), 2.28 (m, 9- 2H), 2.02 (m, 1H), 1.87 (m, 2H), 1.80 (d, J =13.5, yl]pyridin-3-ol 2H), 1.70 (d, J = 9.8, 1H), 1.61 (dd, J = 13.8,7.1, 2H), 1.49 (m, 4H), 1.12 (m, 1H), 0.71 (d, J = 13.5, 1H). 1726-[9-(2-{[(3- 403 δ 9.47 (brs, 1H), 7.51 (dd, J = 9.0, 7.2, 1H), 7.23(d, J = 5.6, methoxythiophen-2- 1H), 6.80 (d, J = 5.5, 1H), 6.52 (d, J =8.9, 1H), yl)methyl]amino}ethyl)- 6.27 (d, J = 7.1, 1H), 4.10 (s, 2H),3.82 (s, 3H), 6-oxaspiro[4.5]decan- 3.73 (dd, J = 6.8, 3.4, 2H), 2.83(dd, J = 11.9, 5.7, 1H), 9- 2.60 (t, J = 10.0, 1H), 2.27 (t, J = 15.0,2H), 2.00 (t, J = 12.3, yl]pyridin-2-ol 2H), 1.65 (m, 10H), 0.97 (d, J =13.4, 1H). 173 2-[(9R)-9-(2-{[(3- 403.2 δ 9.84 (s, 1H), 8.76 (s, 1H),8.32 (d, J = 5.3, 1H), methoxythiophen-2- 7.60 (t, J = 7.7, 1H), 7.52(m, 1H), 7.41 (m, 1H), 7.25 (d, J = 5.5, yl)methyl]amino}ethyl)- 1H),6.81 (d, J = 5.5, 1H), 4.16 (m, 2H), 6-oxaspiro[4.5]decan- 3.82 (m, 4H),3.71 (m, 1H), 3.05 (d, J = 13.4, 2H), 2.85 (d, J = 9.1, 9-yl]-1- 1H),2.53 (s, 1H), 2.27 (d, J = 14.3, 1H), oxidopyridin-1-ium 2.14 (m, 1H),1.99 (t, J = 11.3, 1H), 1.85 (m, 2H), 1.66 (ddd, J = 18.0, 10.0, 5.8,1H), 1.51 (m, 4H), 1.22 (dd, J = 12.3, 6.0, 1H), 0.90 (dt, J = 13.0,8.7, 1H). 174 2-[9-(2-{[(3- 403.2 δ 9.17 (d, J = 50.2, 2H), 8.00 (d, J =6.5, 1H), 7.16 (d, methoxythiophen-2- J = 5.6, 3H), 6.72 (d, J = 5.6,1H), 4.00 (s, 2H), 3.73 (s, yl)methyl]amino}ethyl)- 5H), 2.82 (s, 1H),2.34 (d, J = 39.9, 2H), 2.11 (dd, J = 51.0, 6-oxaspiro[4.5]decan- 13.1,3H), 1.84 (d, J = 13.9, 1H), 1.43 (m, 9H), 9- 0.75 (s, 1H).yl]pyridin-4-ol 175 {2-[(9R)-9-(4- 404 δ 7.24 (s, 3H), 7.03 (dd, J =11.7, 5.6, 2H), 6.80 (d, J = 5.5, fluorophenyl)-6- 1H), 4.00 (s, 2H),3.81 (m, 5H), 2.78 (m, 1H), oxaspiro[4.5]decan-9- 2.39 (m, 1H), 2.17 (m,1H), 2.06 (s, 2H), 1.86 (m, 2H), yl]ethyl}[(3- 1.66 (m, 3H), 1.51 (m,3H), 1.26 (m, 2H), 0.80 (m, methoxythiophen-2- 1H). yl)methyl]amine 176{2-[2,2-dimethyl-4-(4- 406.3 δ 9.43 (d, J = 141.7, 2H), 7.47 (d, J =7.2, 1H), methylphenyl)oxan-4- 7.39 (s, 1H), 7.31 (m, 2H), 6.99 (q, J =8.3, 4H), 3.67 (m, yl]ethyl}({[3- 4H), 2.54 (d, J = 8.4, 1H), 2.20 (d, J= 7.1, 3H), (trifluoromethyl)phenyl]methyl})amine 2.06 (m, 3H), 1.92 (s,2H), 1.60 (td, J = 12.5, 4.7, 1H), 1.46 (m, 2H), 1.08 (s, 3H), 0.55 (s,3H). 177 (1-benzothiophen-2- 407.1 δ 8.51 (dd, J = 5.5, 1.3, 1H), 8.02(d, J = 1.4, 1H), ylmethyl)({2-[(9R)-9- 7.73-7.52 (m, 3H), 7.43 (d, J =1.0, 1H), 7.35-7.23 (m, (pyridin-2-yl)-6- 3H), 3.67 (s, 3H), 2.96 (td, J= 11.5, 5.7, 1H), oxaspiro[4.5]decan-9- 2.56-2.43 (m, 1H), 2.43-2.28 (m,1H), 2.16 (d, J = 13.6, yl]ethyl})amine 3H), 1.89 (d, J = 14.2, 1H),1.73 (ddd, J = 19.7, 11.9, 7.2, 2H), 1.55 (dt, J = 15.0, 5.7, 1H),1.48-1.22 (m, 4H), 1.06 (s, 1H), 0.66 (dt, J = 13.2, 8.9, 1H). 178(1-benzothiophen-3- 407.1 δ 11.71 (s, 2H), 9.34 (d, J = 85.8, 1H), 8.48(d, J = 5.0, ylmethyl)({2-[(9R)-9- 1H), 8.10 (s, 1H), 7.71 (dd, J = 6.2,2.8, 1H), (pyridin-2- 7.58 (ddd, J = 22.1, 9.6, 4.3, 3H), 7.47 (s, 1H),yl)-6- 7.36-7.24 (m, 2H), 4.12 (s, 2H), 3.64 (s, 2H), 2.93 (s, 1H),oxaspiro[4.5]decan-9- 2.51-2.23 (m, 2H), 2.13 (t, J = 14.3, 3H),1.94-1.83 (m, yl]ethyl})amine 1H), 1.80-1.64 (m, 2H), 1.62-1.49 (m, 1H),1.37 (dd, J = 39.4, 7.2, 4H), 1.06 (d, J = 13.0, 1H), 0.64 (dt, J =13.1, 9.0, 1H). 179 [(5-chlorothiophen-2- 408.2 δ 7.11 (dd, J = 8.9,5.2, 2H), 6.94 (dd, J = 15.9, 7.2, yl)methyl]({2-[(9R)-9- 2H), 6.75-6.56(m, 2H), 3.79 (s, 2H), 3.71-3.52 (m, (4- 2H), 2.61 (s, 1H), 2.18 (s,1H), 1.84 (dddd, J = 31.4, fluorophenyl)-6- 25.9, 23.7, 13.1, 12H), 1.58(td, J = 9.4, 4.6, 2H), oxaspiro[4.5]decan-9- 1.39 (ddd, J = 23.7, 14.8,9.2, 5H), 1.17 (s, 2H), 0.69 (dd, J = 8.7, yl]ethyl})amine 5.1, 1H). 1802-{[(2-{2,2-dimethyl-4- 408.3 δ 8.34 (d, J = 45.4, 2H), 7.50 (d, J =8.3, 2H), 7.24 (d, [4- J = 8.2, 2H), 7.10 (s, 1H), 6.77 (m, 3H), 3.80(s, 2H), (trifluoromethyl)phenyl]oxan- 3.66 (d, J = 12.3, 2H), 3.31 (s,3H), 2.63 (s, 1H), 4- 2.09 (dd, J = 26.1, 13.9, 3H), 1.87 (t, J = 10.4,1H), 1.71 (t, yl}ethyl)amino]methyl}phenol J = 10.4, 1H), 1.58 (d, J =14.0, 2H), 1.10 (s, 3H), 0.53 (s, 3H). 181 [(5-chlorothiophen-2- 410.1 δ7.12 (dd, J = 8.9, 5.2, 2H), 6.96 (t, J = 8.6, 2H), yl)methyl]({2-[2,2-6.69 (q, J = 3.8, 2H), 3.79 (s, 2H), 3.63 (dd, J = 12.2, 7.1, diethyl-4-2H), 2.63 (dd, J = 12.2, 7.5, 1H), 2.29-1.77 (m, 8H),(4-fluorophenyl)oxan- 1.67 (td, J = 12.5, 4.7, 1H), 1.44 (dd, J = 24.5,10.8, 4-yl]ethyl})amine 3H), 1.31 (d, J = 7.5, 1H), 0.95 (s, 1H), 0.74(t, J = 7.5, 4H), 0.44 (t, J = 7.4, 3H). 182 {[5-(2- 413.1 δ 9.56 (brs,1H), 8.66 (d, J = 4.7, 1H), 8.09 (t, J = 7.5, methylpropyl)thiophen-1H), 7.62 (d, J = 8.1, 1H), 7.55 (m, 1H), 6.87 (d, J = 3.4,2-yl]methyl}({2-[(9R)- 1H), 6.59 (d, J = 3.4, 1H), 4.08 (m, 2H), 3.75(m, 9- 2H), 2.96 (d, J = 4.8, 1H), 2.57 (d, J = 7.0, 2H), 2.50 (t,(pyridin-2-yl)-6- J = 9.6, 1H), 2.31 (m, 3H), 2.14 (td, J = 13.5, 5.4,1H), oxaspiro[4.5]decan-9- 1.96 (d, J = 14.1, 1H), 1.80 (m, 3H), 1.66(m, 1H), yl]ethyl})amine 1.47 (m, 4H), 1.14 (d, J = 13.0, 1H), 0.89 (d,J = 6.6, 6H), 0.73 (dt, J = 13.6, 9.0, 1H). 183 [(5-butylthiophen-2-413.1 δ 10.87 (brs, 1H), 9.42 (brs, 1H), 8.70 (d, J = 4.8,yl)methyl]({2-[(9R)-9- 1H), 8.17 (t, J = 7.7, 1H), 7.68 (d, J = 8.1,1H), (pyridin-2- 7.62 (m, 1H), 6.85 (d, J = 3.5, 1H), 6.60 (d, J = 3.4,1H), yl)-6- 4.08 (s, 2H), 3.79 (m, 1H), 3.67 (t, J = 10.0, 1H),oxaspiro[4.5]decan-9- 2.97 (d, J = 4.3, 1H), 2.70 (t, J = 7.6, 2H), 2.50(t, J = 9.9, yl]ethyl})amine 1H), 2.33 (m, 3H), 2.16 (td, J = 13.1, 5.0,1H), 1.98 (t, J = 9.4, 1H), 1.80 (t, J = 9.6, 2H), 1.54 (m, 7H), 1.33(dq, J = 14.5, 7.3, 2H), 1.14 (m, 1H), 0.90 (t, J = 7.3, 3H), 0.73 (dt,J = 13.0, 8.9, 1H). 184 {4H,5H,6H- 414 δ 7.20 (m, 2H), 7.01 (dd, J =13.5, 4.7, 2H), 6.65 (s, cyclopenta[b]thiophen- 1H), 3.88 (s, 2H), 3.72(m, 3H), 2.78 (t, J = 7.2, 3H), 2-ylmethyl}({2- 2.61 (t, J = 7.2, 2H),2.34 (dt, J = 14.5, 7.3, 3H), [(9R)-9-(4- 2.15 (d, J = 14.1, 1H), 2.06(d, J = 13.9, 1H), 1.99 (m, 1H), fluorophenyl)-6- 1.89 (m, 2H), 1.78 (m,1H), 1.67 (ddd, J = 18.6, 11.9, oxaspiro[4.5]decan-9- 7.0, 2H), 1.46 (m,4H), 1.25 (m, 1H), 0.79 (dt, J = 13.4, yl]ethyl})amine 8.7, 1H). 185{2-[(9R)-9-(pyridin-2- 415 δ 9.37 (s, 1H), 8.65 (dd, J = 5.3, 1.3, 1H),8.12 (td, J = 7.9, yl)-6- 1.6, 1H), 7.65 (d, J = 8.2, 1H), 7.56 (dd, J =7.1, oxaspiro[4.5]decan-9- 5.7, 1H), 6.34 (s, 1H), 5.94 (s, 1H), 4.16(dt, J = 8.2, yl]ethyl}({2H,3H- 6.0, 4H), 4.05 (m, 2H), 3.77 (m, 2H),3.06 (dd, J = 17.1, thieno[3,4- 11.1, 1H), 2.61 (t, J = 8.9, 1H), 2.29(m, 4H), b][1,4]dioxin-5- 1.99 (t, J = 8.8, 1H), 1.82 (ddd, J = 13.6,9.4, 4.3, 2H), ylmethyl})amine 1.67 (m, 1H), 1.48 (ddd, J = 14.5, 12.7,6.9, 4H), 1.19 (m, 1H), 0.74 (dt, J = 13.3, 9.0, 1H). 186{2-[2,2-dimethyl-4-(4- 416.3 δ 8.66 (d, J = 167.7, 2H), 7.92 (m, 1H),7.52 (m, 3H), methylphenyl)oxan-4- 7.05 (s, 4H), 4.21 (s, 2H), 3.71 (m,2H), 3.49 (s, 1H), yl]ethyl}[(2- 3.06 (s, 3H), 2.85 (s, 1H), 2.47 (d, J= 4.8, 1H), methanesulfonylphenyl)methyl]amine 2.20 (m, 4H), 2.09 (dd, J= 13.9, 2.1, 1H), 1.94 (d, J = 4.6, 1H), 1.72 (s, 1H), 1.55 (m, 2H),1.10 (s, 3H), 0.57 (s, 3H). 187 [(4-bromofuran-2- 419 δ 9.52 (s, 1H),8.77 (s, 1H), 8.38 (s, 1H), 7.83 (d, J = 7.6, yl)methyl]({2-[(9R)-9-2H), 7.40 (s, 1H), 6.51 (s, 1H), 4.09 (s, 2H), (pyridin-2- 3.78 (d, J =48.0, 2H), 3.03 (s, 1H), 2.63-2.41 (m, 2H), yl)-6- 2.33 (dd, J = 28.3,13.9, 3H), 2.09 (d, J = 14.2, 1H), oxaspiro[4.5]decan-9- 1.90 (s, 2H),1.82-1.63 (m, 1H), 1.53 (ddd, J = 12.9, yl]ethyl})amine 10.9, 4.5, 4H),1.19 (s, 1H), 0.79 (dt, J = 13.0, 8.9, 1H). 188 {2-[(9R)-9-(4- 420 δ7.22 (dd, J = 8.9, 5.2, 2H), 7.05 (t, J = 8.6, 2H), fluorophenyl)-6-6.85 (dd, J = 10.8, 3.7, 2H), 3.95 (s, 2H), 3.75 (d, J = 4.6,oxaspiro[4.5]decan-9- 2H), 2.75 (s, 1H), 2.47 (s, 3H), 2.32 (s, 1H),2.17 (d, J = 14.4, yl]ethyl}({[5- 1H), 2.09 (d, J = 13.8, 1H), 1.99 (dt,J = 12.3, (methylsulfanyl)thiophen- 6.4, 1H), 1.91 (d, J = 13.9, 2H),1.80 (d, J = 10.5, 1H), 2- 1.74-1.61 (m, 2H), 1.49 (dt, J = 18.7, 11.7,4H), yl]methyl})amine 1.26 (s, 1H), 0.89-0.75 (m, 1H). 189{2-[(9R)-9-(pyridin-2- 420.3 δ 8.83-8.56 (m, 2H), 8.35 (t, J = 7.6, 1H),7.96 (dd, J = 19.3, yl)-6- 8.7, 1H), 7.87-7.75 (m, 2H), 7.71 (t, J =9.2, oxaspiro[4.5]decan-9- 1H), 4.16 (s, 2H), 3.84 (dd, J = 8.5, 4.4,1H), 3.71 (t, J = 10.0, yl]ethyl}({[6- 1H), 3.07 (dd, J = 11.7, 6.8,1H), 2.55 (dt, J = 25.6, (trifluoromethyl)pyridin- 11.9, 2H), 2.43-2.21(m, 3H), 2.10 (d, J = 14.2, 3- 1H), 1.90 (ddd, J = 26.1, 14.9, 6.7, 2H),yl]methyl})amine 1.76-1.62 (m, 1H), 1.60-1.34 (m, 4H), 1.33-1.09 (m,1H), 0.76 (dt, J = 12.8, 8.8, 1H). 190 [(5-bromofuran-2- 421 δ 8.75 (d,J = 4.8, 1H), 8.24 (t, J = 7.7, 1H), yl)methy]({2-[(9R)-9- 7.86-7.58 (m,2H), 6.44 (d, J = 3.3, 1H), 6.28 (d, J = 3.3, (pyridin-2- 1H), 4.07 (s,2H), 3.94-3.79 (m, 1H), 3.72 (t, J = 10.1, yl)-6- 1H), 3.01 (dd, J =11.1, 6.0, 1H), 2.56 (t, J = 9.9, oxaspiro[4.5]decan-9- 1H), 2.49-2.11(m, 4H), 2.05 (d, J = 14.1, 1H), yl]ethyl})amine 1.88 (ddd, J = 18.8,11.0, 6.5, 2H), 1.78-1.31 (m, 5H), 1.31-1.07 (m, 1H), 0.77 (dt, J =13.1, 8.9, 1H) 191 (2-{2,2-dimethyl-4-[4- 422.3 δ 8.49 (d, J = 118.7,2H), 7.50 (d, J = 8.3, 2H), (trifluoromethyl)phenyl]oxan- 7.25 (dd, J =10.3, 4.6, 3H), 6.96 (dd, J = 7.5, 1.5, 1H), 4- 6.79 (ddd, J = 22.1,14.4, 4.4, 2H), 6.08 (s, 1H), 3.84 (d, J = 9.2, yl}ethyl)[(2- 2H), 3.68(m, 5H), 2.64 (s, 1H), 2.09 (m, 3H), methoxyphenyl)methyl]amine 1.90 (m,1H), 1.77 (dd, J = 12.7, 4.5, 1H), 1.58 (ddd, J = 14.0, 10.8, 10.1, 2H),1.12 (s, 3H), 0.55 (s, 3H). 192 {2-[2,2,6,6- 422.3 δ 8.79-8.63 (m, 2H),8.31 (t, J = 7.9, 1H), tetramethyl-4-(pyridin- 8.05-7.90 (m, 2H),7.87-7.61 (m, 2H), 4.16 (s, 2H), 2-yl)oxan-4- 2.82 (dd, J = 10.0, 6.6,2H), 2.54 (d, J = 14.7, 2H), yl]ethyl}({[6- 2.46-2.30 (m, 2H), 1.95 (d,J = 14.8, 2H), 1.32 (s, 5H), (trifluoromethyl)pyridin- 0.98 (s, 5H). 3-yl]methyl})amine 193 {[5-(furan-2- 423.1 δ 9.59 (s, 1H), 8.56 (d, J =4.7, 1H), 8.05 (t, J = 7.4, yl)thiophen-2- 1H), 7.57 (d, J = 8.1, 1H),7.46 (dd, J = 12.2, 6.3, 1H), yl]methyl}({2-[(9R)-9- 7.35-7.26 (m, 1H),6.93 (dd, J = 19.9, 3.7, 2H), (pyridin-2-yl)-6- 6.46-6.30 (m, 2H), 4.08(s, 2H), 3.78-3.54 (m, 2H), oxaspiro[4.5]decan-9- 3.00-2.81 (m, 1H),2.46 (t, J = 9.7, 1H), 2.30 (t, J = 10.6, yl]ethyl})amine 1H), 2.13(ddd, J = 17.3, 16.1, 9.3, 3H), 1.89 (d, J = 14.2, 1H), 1.72 (ddd, J =13.9, 9.5, 4.3, 2H), 1.54 (dd, J = 21.6, 14.5, 1H), 1.48-1.23 (m, 4H),1.06 (d, J = 13.2, 1H), 0.65 (dt, J = 13.3, 8.9, 1H). 194[(5-chlorothiophen-2- 423.2 δ 7.13 (dd, J = 8.9, 5.1, 2H), 6.95 (dd, J =15.5, 6.8, yl)methyl]({2-[4-(4- 2H), 6.69 (q, J = 3.9, 2H), 3.81 (s,2H), 3.62 (d, J = 13.8, fluorophenyl)-1- 2H), 2.68 (m, 1H), 2.11 (dd, J= 22.2, 13.8, 3H), oxaspiro[5.5]undecan- 1.84 (m, 1H), 1.54 (m, 4H),1.30 (m, 4H), 1.05 (d, J = 11.4, 4- 4H), 0.63 (m, 1H). yl]ethyl})amine195 (1-benzothiophen-2- 424 δ 9.53 (d, J = 105.8, 2H), 7.77-7.66 (m,2H), ylmethyl)({2-[(9R)-9-(4- 7.36-7.32 (m, 2H), 7.15 (dd, J = 8.8, 5.2,3H), 6.96 (t, J = 8.6, fluorophenyl)-6- 2H), 3.96 (s, 2H), 3.75-3.63 (m,2H), 2.75 (s, oxaspiro[4.5]decan-9- 1H), 2.33 (s, 1H), 2.19-2.16 (m,0H), 2.15-1.71 (m, yl]ethyl})amine 6H), 1.71-1.29 (m, 6H), 1.22 (s, 1H),0.77 (dt, J = 13.5, 9.0, 1H). 196 (1-benzothiophen-3- 424 δ 8.67 (d, J =139.8, 2H), 7.76-7.61 (m, 1H), ylmethyl)({2-[(9R)-9-(4- 7.56-7.39 (m,1H), 7.34-7.25 (m, 3H), 6.98 (dd, J = 8.8, fluorophenyl)-6- 5.1, 2H),6.84 (t, J = 8.6, 2H), 3.89 (s, 2H), oxaspiro[4.5]decan-9- 3.71-3.54 (m,2H), 2.66 (s, 1H), 2.21 (s, 1H), 2.07-1.89 (m, yl]ethyl})amine 2H),1.89-1.60 (m, 4H), 1.60-1.45 (m, 2H), 1.44-1.24 (m, 4H), 1.19-1.07 (m,1H), 0.67 (dt, J = 13.8, 8.9, 1H). 197 [(5-fluoro-1- 425 δ 8.47 (s, 1H),7.69 (s, 2H), 7.42 (d, J = 9.2, 1H), benzothiophen-2- 7.30 (dd, J =10.5, 9.5, 3H), 7.13 (s, 2H), 4.21 (d, J = 13.3, yl)methyl]({2-[(9R)-9-2H), 3.73 (s, 2H), 3.16-2.91 (m, 1H), 2.82-2.52 (m, (pyridin-2-yl)-6-1H), 2.27 (d, J = 14.8, 2H), 2.21-2.09 (m, 1H), oxaspiro[4.5]decan-9-2.08-1.94 (m, 1H), 1.85 (d, J = 13.6, 1H), 1.65 (s, 4H), yl]ethyl})amine1.43 (d, J = 38.4, 3H), 1.18-1.02 (m, 1H), 0.75-0.60 (m, 1H). 198 [(5-425.1 δ 12.19-12.13 (m, 0H), 8.69 (d, J = 4.7, 1H), 8.18 (s,cyclopentylthiophen-2- 1H), 7.80-7.59 (m, 2H), 6.90 (d, J = 3.5, 1H),yl)methyl]({2-[(9R)-9- 6.67 (d, J = 2.9, 1H), 4.14 (s, 2H), 3.82 (d, J =12.7, 2H), (pyridin-2-yl)-6- 3.73, (d, J = 9.7, 1H), 3.17 (t, J = 8.3,1H), 3.02 (s, 1H), oxaspiro[4.5]decan-9- 2.58 (s, 1H), 2.31 (d, J =14.1, 4H), 2.05 (dd, J = 33.0, yl]ethyl})amine 10.0, 3H), 1.90-1.74 (m,4H), 1.68 (dt, J = 12.1, 9.1, 3H), 1.51 (ddd, J = 13.4, 10.8, 5.9, 6H),1.18 (s, 1H), 0.79 (s, 1H). 199 [(4- 427.3 δ 8.59 (d, J = 4.9, 1H), 8.18(t, J = 7.4, 1H), phenylphenyl)methyl]({2- 7.75-7.52 (m, 2H), 7.47-7.38(m, 4H), 7.35-7.29 (m, [(9R)-9-(pyridin-2- 2H), 7.29-7.21 (m, 3H), 3.91(s, 2H), 3.70 (dt, J = 12.3, yl)-6- 4.2, 1H), 3.57 (t, J = 9.7, 1H),2.92 (s, 1H), oxaspiro[4.5]decan-9- 2.40 (dd, J = 26.0, 12.7, 2H),2.30-2.04 (m, 3H), yl]ethyl})amine 2.04-1.84 (m, 1H), 1.76 (ddd, J =27.2, 15.3, 6.8, 2H), 1.65-1.21 (m, 5H), 1.07 (dd, J = 14.4, 5.6, 1H),0.67 (dt, J = 13.0, 9.0, 1H). 200 [(3- 427.3 δ 8.44 (d, J = 4.1, 1H),7.96 (t, J = 7.1, 1H), phenylphenyl)methyl]({2- 7.53-7.43 (m, 5H),7.42-7.26 (m, 3H), 7.19 (s, 3H), [(9R)-9-(pyridin-2- 3.94 (s, 1H),3.82-3.45 (m, 2H), 2.73 (s, 2H), 2.44 (s, 1H), yl)-6- 2.31 (d, J = 10.6,1H), 2.15 (d, J = 13.2, 3H), 1.86 (d, J = 14.1, oxaspiro[4.5]decan-9-1H), 1.70 (t, J = 9.7, 2H), 1.56 (s, 1H), yl]ethyl})amine 1.50-1.22 (m,5H), 1.06 (s, 1H), 0.66 (dd, J = 13.3, 9.0, 1H). 201 benzyl({2-[9-(4-428.2 δ 9.51 (s, 1H), 9.15 (s, 1H), 7.42 (d, J = 8.6, 2H),bromophenyl)-6- 7.30 (m, 3H), 7.16 (dd, J = 7.3, 2.1, 2H), 7.06 (d, J =8.7, oxaspiro[4.5]decan-9- 2H), 3.68 (m, 4H), 2.62 (m, 1H), 2.19 (m,1H), yl]ethyl})amine 2.04 (dd, J = 22.4, 13.9, 2H), 1.93 (m, 1H), 1.85(m, 3H), 1.60 (m, 2H), 1.45 (ddd, J = 21.1, 16.1, 8.8, 5H), 1.25 (m,2H), 0.77 (dt, J = 13.2, 8.7, 1H). 202 2-amino-4-chloro-5- 431 1H NMR(400 MHz, CD3CN) δ 8.57 (dd, J = 4.9, 1.0, [({2-[(9R)-9-(pyridin-2- 1H),7.83 (m, 1H), 7.48 (d, J = 8.1, 1H), 7.31 (ddd, J = 7.5, yl)-6- 4.9,0.9, 1H), 6.13 (s, 2H), 4.06 (s, 2H), 3.69 (m, oxaspiro[4.5]decan-9-2H), 2.96 (m, 1H), 2.42 (m, 2H), 2.08 (m, 2H),yl]ethyl}amino)methyl]thiophene- 1.92 (m, 1H), 1.87 (d, J = 13.5, 1H),1.57 (m, 8H), 1.10 (m, 3- 1H), 0.71 (m, 1H). carbonitrile 203{2-[(9R)-9-(4- 432 δ 7.21 (dd, J = 9.0, 5.1, 2H), 7.03 (t, J = 8.6, 2H),fluorophenyl)-6- 6.33 (s, 1H), 4.13 (s, 4H), 3.90 (s, 2H), 3.74 (m, 2H),oxaspiro[4.5]decan-9- 3.01 (brs, 1H), 2.77 (t, J = 13.7, 1H), 2.35 (m,1H), 2.17 (d, yl]ethyl}({2H,3H- J = 14.0, 1H), 2.02 (dt, J = 14.7, 9.5,2H), 1.89 (m, thieno[3,4- 2H), 1.78 (d, J = 10.1, 1H), 1.68 (ddd, J =16.9, 10.6, b][1,4]dioxin-5- 5.8, 2H), 1.46 (ddd, J = 17.8, 10.0, 5.9,4H), 1.25 (m, ylmethyl})amine 1H), 0.79 (dt, J = 13.5, 8.8, 1H). 204[(4-phenylthiophen-2- 433.1 δ 9.71 (s, 4H), 8.53 (d, J = 5.0, 1H), 8.09(t, J = 7.6, yl)methyl]({2-[(9R)-9- 1H), 7.62 (d, J = 8.1, 1H),7.54-7.44 (m, 1H), (pyridin-2-yl)-6- 7.43-7.35 (m, 2H), 7.32-7.19 (m,5H), 4.12 (s, 2H), oxaspiro[4.5]decan-9- 3.77-3.52 (m, 2H), 3.00-2.76(m, 1H), 2.41 (dt, J = 25.0, yl]ethyl})amine 11.5, 2H), 2.18 (t, J =17.1, 3H), 1.90 (d, J = 14.1, 1H), 1.73 (ddd, J = 19.6, 11.4, 6.9, 2H),1.55 (dd, J = 10.0, 4.9, 1H), 1.48-1.26 (m, 4H), 1.04 (s, 1H), 0.72-0.56(m, 1H). 205 [(5-phenylthiophen-2- 433.1 δ 9.74 (brs, 1H), 7.62 (d, J =8.1, 1H), 7.50 (m, 3H), yl)methyl]({2-[(9R)-9- 7.37 (m, 2H), 7.31 (m,1H), 7.12 (d, J = 3.7, 1H), (pyridin-2-yl)-6- 7.04 (d, J = 3.7, 1H),5.23 (brs, 1H), 4.19 (mz, 2H), oxaspiro[4.5]decan-9- 3.72 (m, 2H), 3.02(d, J = 6.5, 1H), 2.59 (t, J = 9.1, 1H), yl]ethyl})amine 2.39 (t, J =10.1, 1H), 2.22 (dd, J = 29.2, 10.0, 3H), 1.96 (d, J = 14.1, 1H), 1.80(t, J = 11.0, 2H), 1.62 (dd, J = 14.1, 7.4, 1H), 1.44 (ddd, J = 16.8,16.4, 7.5, 4H), 1.13 (m, 1H), 0.73 (dt, J = 12.7, 8.8, 1H). 206 [(5- 435δ 8.67 (d, J = 5.0, 1H), 8.32 (t, J = 8.0, 1H), 7.79 (d, J = 7.9,methanesulfonylthiophen- 2H), 7.59 (d, J = 3.8, 1H), 7.22 (d, J = 3.8,1H), 2-yl)methyl]({2- 4.31 (d, J = 6.2, 2H), 3.84 (s, 1H), 3.74 (s, 1H),3.18 (s, [(9R)-9- 1H), 3.05 (s, 2H), 2.54 (t, J = 10.3, 2H), 2.31 (d, J= 13.3, (pyridin-2-yl)-6- 2H), 2.14-2.00 (m, 2H), 1.89 (d, J = 13.8,3H), oxaspiro[4.5]decan-9- 1.81-1.64 (m, 1H), 1.64-1.37 (m, 3H), 1.28(s, 2H), yl]ethyl})amine 0.81 (d, J = 13.2, 1H). 207[(4-bromothiophen-3- 435 δ 11.51 (s, 1H), 9.44 (s, 1H), 8.69-8.58 (m,1H), yl)methyl]({2-[(9R)-9- 8.14 (td, J = 8.0, 1.6, 1H), 7.68-7.56 (m,2H), (pyridin-2- 7.52 (d, J = 3.4, 1H), 7.21 (d, J = 3.3, 1H), 4.01 (s,2H), yl)-6- 3.82-3.54 (m, 2H), 2.97 (td, J = 11.5, 5.7, 1H),oxaspiro[4.5]decan-9- 2.62-2.43 (m, 1H), 2.41-2.12 (m, 4H), 2.02-1.89(m, yl]ethyl})amine 1H), 1.78 (ddd, J = 18.6, 11.9, 6.5, 2H), 1.60 (dt,J = 13.5, 7.7, 1H), 1.55-1.30 (m, 4H), 1.10 (d, J = 4.1, 0H), 0.67 (dt,J = 13.1, 8.9, 1H). 208 [(4-bromothiophen-2- 435.1 δ 8.59 (d, J = 4.0,1H), 8.13 (t, J = 7.1, 1H), 7.65 (d, J = 8.2, yl)methyl]({2-[(9R)-9-1H), 7.59 (m, 1H), 7.23 (d, J = 1.4, 1H), 7.04 (d, (pyridin-2- J = 1.2,1H), 4.19 (s, 2H), 3.75 (m, 2H), 3.01 (m, 1H), yl)-6- 2.84 (s, 1H), 2.60(m, 1H), 2.40 (m, 1H), 2.25 (d, J = 13.0, oxaspiro[4.5]decan-9- 3H),1.97 (d, J = 14.0, 1H), 1.83 (d, J = 9.4, 2H), yl]ethyl})amine 1.67 (m,1H), 1.48 (dd, J = 24.0, 15.8, 4H), 1.17 (brs, 1H), 0.77 (m, 1H). 209[(5-bromothiophen-2- 435.1 δ 8.61 (d, J = 4.3, 1H), 8.14 (t, J = 7.9,1H), 7.65 (d, J = 8.1, yl)methyl]({2-[(9R)-9- 1H), 7.60 (m, 1H), 6.94(d, J = 3.8, 1H), 6.89 (d, (pyridin-2- J = 3.8, 1H), 4.14 (s, 2H), 3.76(m, 3H), 2.99 (m, 1H), yl)-6- 2.58 (m, 1H), 2.38 (d, J = 9.8, 1H), 2.26(d, J = 13.9, oxaspiro[4.5]decan-9- 3H), 1.97 (d, J = 14.1, 1H), 1.82(t, J = 9.7, 2H), yl]ethyl})amine 1.67 (s, 1H), 1.47 (m, 4H), 1.16 (s,1H), 0.75 (dt, J = 13.4, 9.2, 1H). 210 [(2-bromothiophen-3- 436 δ 8.66(d, J = 5.3, 1H), 8.21 (d, J = 7.2, 1H), yl)methyl]({2-[(9R)-9-7.85-7.58 (m, 2H), 7.33 (d, J = 5.7, 1H), 7.09 (d, J = 5.7, (pyridin-2-1H), 4.02-3.63 (m, 3H), 3.10-2.97 (m, 2H), 2.61 (t, yl)-6- J = 9.1, 1H),2.43 (d, J = 11.0, 1H), 2.30 (d, J = 13.6, oxaspiro[4.5]decan-9- 3H),2.04 (s, 1H), 1.94-1.80 (m, 2H), 1.69 (s, 1H), yl]ethyl})amine 1.64-1.40(m, 4H), 1.20 (s, 1H), 0.86-0.68 (m, 1H). 211 [(5-bromofuran-2- 436 δ9.07 (d, J = 116.7, 2H), 7.16-7.06 (m, 2H), yl)methyl]({2-[(9R)-9-7.01-6.89 (m, 2H), 6.25 (d, J = 3.4, 1H), 6.17 (s, 1H), (4- 3.83 (s,2H), 3.76-3.58 (m, 2H), 2.66 (s, 1H), 2.23 (s, 1H), fluorophenyl)-6-2.09 (d, J = 14.0, 1H), 2.04-1.96 (m, 1H), oxaspiro[4.5]decan-9-1.95-1.66 (m, 4H), 1.66-1.50 (m, 2H), 1.50-1.28 (m, yl]ethyl})amine 4H),1.28-1.13 (m, 1H), 0.71 (dt, J = 13.6, 8.8, 1H). 212 {2-[(9R)-9-(4-437.2 δ 8.63 (s, 1H), 7.83 (d, J = 8.3, 1H), 7.68 (d, J = 8.0,fluorophenyl)-6- 1H), 7.29 (s, 1H), 7.21 (dd, J = 8.9, 5.1, 3H), 7.05(s, oxaspiro[4.5]decan-9- 2H), 3.93 (s, 2H), 3.75 (dd, J = 11.3, 7.3,2H), yl]ethyl}({[6- 2.84-2.58 (m, 1H), 2.44-2.04 (m, 10H), 2.02-1.75 (m,(trifluoromethyl)pyridin- 5H), 1.74-1.56 (m, 3H), 1.59-1.33 (m, 5H), 3-1.33-1.19 (m, 1H), 0.78 (d, J = 13.6, 1H). yl]methyl})amine 213[(4-bromofuran-2- 437.9 δ 7.38 (d, J = 0.6, 1H), 7.28 (s, 1H), 7.22 (d,J = 5.2, yl)methyl]({2-[(9R)-9- 2H), 7.08 (d, J = 8.5, 2H), 3.75 (dd, J= 11.7, 7.1, 2H), (4-fluorophenyl)-6- 2.73 (s, 1H), 2.30 (d, J = 4.5,2H), 2.17 (d, J = 13.5, oxaspiro[4.5]decan-9- 1H), 2.10 (d, J = 13.9,1H), 2.05-1.95 (m, 1H), yl]ethyl})amine 1.94 (s, 2H), 1.79 (d, J = 9.8,1H), 1.74-1.62 (m, 2H), 1.49 (dt, J = 16.4, 10.6, 4H), 1.28 (s, 2H),0.80 (d, J = 13.7, 1H). 214 {2-[(9R)-9-(pyridin-2- 439 δ 8.52 (d, J =5.3, 1H), 7.96 (t, J = 7.9, 1H), 7.50 (d, J = 8.1, yl)-6- 1H), 7.40 (dd,J = 16.2, 10.4, 1H), oxaspiro[4.5]decan-9- 7.24-7.10 (m, 1H), 7.03 (dd,J = 3.6, 1.0, 1H), 6.98-6.81 (m, yl]ethyl}({[5-(thiophen- 3H), 4.07 (s,2H), 3.80-3.49 (m, 2H), 2.90 (d, J = 11.1, 2-yl)thiophen-2- 2H), 2.16(s, 5H), 1.87 (d, J = 14.0, 1H), yl]methyl})amine 1.71 (dd, J = 11.5,7.2, 2H), 1.54 (d, J = 6.1, 1H), 1.36 (ddd, J = 16.8, 12.9, 6.1, 5H),1.05 (s, 1H), 0.82-0.54 (m, 1H). 215 {2-[2,2-diethyl-4-(4- 439.3 δ 8.62(s, 1H), 7.84 (d, J = 8.2, 1H), 7.66 (d, J = 8.2, fluorophenyl)oxan-4-1H), 7.20 (m, 1H), 7.04 (s, 2H), 3.90 (s, 2H), 3.71 (d, J = 12.1,yl]ethyl}({[6- 2H), 2.77 (m, 1H), 2.19 (m, 3H), 1.98 (m, 1H),(trifluoromethyl)pyridin- 1.68 (M, 3H), 1.40 (d, J = 7.6, 2H), 1.04 (s,1H), 3- 0.83 (t, J = 7.5, 4H), 0.54 (d, J = 7.3, 3H). yl]methyl})amine216 [(5-chloro-1- 442 δ 8.61 (d, J = 4.9, 1H), 8.44 (s, 1H), 8.17 (s,1H), benzothiophen-3- 7.93 (d, J = 5.5, 1H), 7.69 (d, J = 8.1, 1H), 7.60(s, 1H), yl)methyl]({2-[(9R)-9- 7.50 (d, J = 5.5, 1H), 7.28 (s, 1H),3.82 (s, 3H), 3.17 (dd, J = 16.8, (pyridin-2-yl)-6- 10.9, 1H), 2.75 (t,J = 8.9, 1H), 2.47 (t, J = 9.7, oxaspiro[4.5]decan-9- 1H), 2.32 (d, J =13.9, 3H), 2.10-1.98 (m, 1H), yl]ethyl})amine 1.87 (dd, J = 12.1, 7.1,2H), 1.78-1.62 (m, 1H), 1.48 (dd, J = 23.5, 18.9, 5H), 1.18 (s, 1H),0.77 (dt, J = 13.2, 9.0, 1H). 217 [(5-bromo-4- 449 δ 10.10-9.21 (m, 1H),8.53 (d, J = 3.9, 1H), 7.90 (td, methylthiophen-2- J = 7.9, 1.6, 1H),7.45 (d, J = 8.1, 1H), 7.38 (dd, J = 7.0, yl)methyl]({2-[(9R)-9- 5.4,1H), 6.69 (s, 1H), 4.02-3.86 (m, 2H), (pyridin-2-yl)-6- 3.74-3.55 (m,2H), 2.85 (dd, J = 11.4, 5.9, 1H), oxaspiro[4.5]decan-9- 2.47-2.33 (m,1H), 2.31-2.09 (m, 3H), 2.09-1.93 (m, 4H), yl]ethyl})amine 1.87 (d, J =14.0, 1H), 1.69 (dt, J = 14.4, 6.1, 2H), 1.57 (d, J = 5.4, 1H), 1.38(ddd, J = 26.7, 14.6, 8.4, 4H), 1.04 (s, 1H), 0.73-0.56 (m, 1H). 218[(4-bromo-5- 449 δ 8.72 (d, J = 4.9, 1H), 8.26 (d, J = 7.7, 1H), 7.74(dd, methylthiophen-2- J = 16.7, 7.1, 2H), 6.92 (s, 1H), 4.21 (d, 1H),yl)methyl]({2-[(9R)-9- 3.90-3.78 (m, 2H), 3.74 (d, J = 9.6, 1H), 3.02(s, 1H), (pyridin-2-yl)-6- 2.51 (dd, J = 52.4, 11.0, 2H), 2.39-2.16 (m,6H), 2.05 (d, oxaspiro[4.5]decan-9- J = 13.8, 1H), 1.87 (d, J = 9.5,2H), 1.69 (s, 1H), yl]ethyl})amine 1.63-1.41 (m, 4H), 1.24 (d, J = 30.9,1H), 0.81 (s, 1H). 219 [(3-bromo-5- 449 δ 8.61 (d, J = 4.9, 1H), 8.02(d, J = 7.9, 1H), methylthiophen-2- 7.69-7.41 (m, 2H), 6.68 (d, J = 1.0,1H), 4.23 (q, J = 14.2, yl)methyl]({2-[(9R)-9- 2H), 3.90-3.59 (m, 2H),3.10 (s, 1H), 2.75 (m, 2H), (pyridin-2-yl)-6- 2.36-2.13 (m, 5H), 1.96(d, J = 13.9, 1H), 1.82 (d, J = 9.9, oxaspiro[4.5]decan-9- 2H),1.75-1.62 (m, 1H), 1.62-1.38 (m, 4H), yl]ethyl})amine 1.24-1.05 (m, 1H),0.74 (d, J = 13.2, 1H). 220 [(4-bromo-3- 449 δ 8.61 (d, J = 5.2, 1H),8.09 (t, J = 7.7, 1H), methylthiophen-2- 7.71-7.49 (m, 2H), 7.30 (s,1H), 4.21 (d, J = 4.3, 2H), yl)methyl]({2-[(9R)-9- 4.00-3.59 (m, 2H),3.05 (s, 1H), 2.64 (s, 1H), 2.31 (d, J = 14.5, (pyridin-2-yl)-6- 2H),2.25 (d, J = 13.7, 2H), 2.18 (s, 3H), 1.96 (d, oxaspiro[4.5]decan-9- J =13.9, 1H), 1.82 (dd, J = 12.0, 7.2, 2H), 1.68 (s, 1H), yl]ethyl})amine1.61-1.40 (m, 4H), 1.17 (s, 1H), 0.92-0.64 (m, 1H). 221{2-[4-(4-fluorophenyl)- 451.2 δ 8.52 (s, 1H), 7.73 (d, J = 9.6, 1H),7.57 (d, J = 8.0, 1- 1H), 7.11 (dd, J = 9.0, 5.2, 2H), 6.94 (t, J = 8.4,2H), oxaspiro[5.5]undecan- 3.83 (s, 2H), 3.63 (d, J = 18.0, 2H), 2.69(m, 1H), 4- 2.12 (t, J = 13.9, 3H), 1.70 (m, 5H), 1.31 (d, J = 18.3,4H), yl]ethyl}({[6- 1.03 (s, 4H), 0.57 (m, 1H).(trifluoromethyl)pyridin- 3- yl]methyl})amine 222 [(4-bromothiophen-3-451.9 δ 9.26 (d, J = 136.7, 2H), 7.39 (dd, J = 22.6, 19.3,yl)methyl]({2-[(9R)-9- 2H), 7.10 (dd, J = 8.8, 5.2, 2H), 6.92 (dd, J =10.6, 6.6, (4-fluorophenyl)-6- 2H), 3.82 (s, 2H), 3.71-3.53 (m, 2H),2.64 (s, 1H), oxaspiro[4.5]decan-9- 2.20 (s, 1H), 2.05 (d, J = 14.1,1H), 1.97 (d, J = 13.9, yl]ethyl})amine 1H), 1.89 (td, J = 12.6, 4.6,1H), 1.83-1.64 (m, 3H), 1.57 (ddd, J = 14.0, 9.6, 4.7, 2H), 1.49-1.25(m, 4H), 1.17 (d, J = 13.2, 1H), 0.69 (dt, J = 13.8, 8.8, 1H). 223[(4-bromothiophen-2- 452.1 δ 9.38 (d, J = 89.0, 2H), 7.16-7.03 (m, 3H),6.96 (t, yl)methyl]({2-[(9R)-9- J = 8.6, 2H), 6.84 (d, J = 1.3, 1H),3.86 (s, 2H), (4- 3.70-3.55 (m, 2H), 2.62 (dd, J = 12.1, 7.7, 1H), 2.18(dd, J = 11.9, fluorophenyl)-6- 7.8, 1H), 2.02 (dd, J = 32.5, 14.0, 2H),oxaspiro[4.5]decan-9- 1.91-1.63 (m, 4H), 1.64-1.50 (m, 2H), 1.49-1.25(m, yl]ethyl})amine 4H), 1.16 (dd, J = 14.0, 6.1, 1H), 0.69 (dt, J =13.5, 8.8, 1H). 224 [(5-bromothiophen-2- 452.1 δ 9.31 (d, J = 92.6, 2H),7.15-7.04 (m, 2H), 6.95 (t, yl)methyl]({2-[(9R)-9- J = 8.6, 2H), 6.82(d, J = 3.8, 1H), 6.67 (d, J = 3.8, 1H), (4- 3.82 (s, 2H), 3.70-3.53 (m,2H), 3.44 (s, 1H), fluorophenyl)-6- 2.62 (dd, J = 12.0, 7.6, 1H), 2.18(dd, J = 11.8, 7.9, 1H), oxaspiro[4.5]decan-9- 2.02 (dd, J = 31.6, 14.0,2H), 1.93-1.64 (m, 4H), yl]ethyl})amine 1.57 (ddd, J = 12.1, 8.5, 3.8,2H), 1.52-1.25 (m, 4H), 1.16 (dd, J = 14.9, 5.1, 1H), 0.69 (dt, J =13.6, 8.8, 1H). 225 dibenzyl({2-[(9R)-9-(4- 458.3 δ 7.27 (m, 17H), 7.00(dd, J = 8.9, 5.2, 2H), 6.86 (t, J = 8.6, fluorophenyl)-6- 2H), 4.24 (s,2H), 3.90 (m, 2H), 3.55 (d, J = 3.4, oxaspiro[4.5]decan-9- 2H), 2.59 (m,1H), 2.22 (m, 12H), 1.86 (dd, J = 75.2, yl]ethyl})amine 14.8, 7H), 1.59(dd, J = 44.5, 9.1, 2H), 1.38 (m, 6H), 1.18 (s, 1H), 1.11 (s, 1H), 0.68(m, 1H). 226 dibenzyl({2-[2,2- 460.3 δ 7.27 (d, J = 34.4, 7H), 7.18 (s,4H), 6.98 (dd, J = 8.9, diethyl-4-(4- 5.2, 2H), 6.84 (t, J = 8.6, 2H),4.25 (s, 2H), 3.85 (d, J = 46.4, fluorophenyl)oxan-4- 2H), 3.53 (m, 2H),2.57 (d, J = 4.7, 2H), 2.12 (d, yl]ethyl})amine J = 4.0, 2H), 1.97 (m,3H), 1.73 (d, J = 4.8, 1H), 1.44 (s, 1H), 1.38 (dd, J = 13.8, 7.5, 3H),1.23 (m, 1H), 0.90 (m, 1H), 0.70 (dt, J = 10.8, 7.4, 4H), 0.40 (t, J =7.4, 3H). 227 [(4-bromo-3- 465.9 δ 7.19 (dd, J = 8.9, 5.1, 2H), 7.04 (t,J = 8.6, 2H), methylthiophen-2- 3.94 (d, J = 16.3, 2H), 3.72 (m, 2H),2.72 (dd, J = 13.8, 6.5, yl)methyl]({2-[(9R)-9- 1H), 2.31 (m, 1H), 2.15(d, J = 12.1, 2H), 2.07 (s, 3H), (4-fluorophenyl)-6- 1.90 (m, 5H), 1.65(m, 2H), 1.47 (m, 4H), 1.25 (s, 1H), oxaspiro[4.5]decan-9- 0.78 (m, 1H).yl]ethyl})amine 228 [(4-bromo-5- 465.9 δ 9.06 (d, J = 100.4, 2H),7.15-7.04 (m, 2H), methylthiophen-2- 6.95 (s, 2H), 6.68 (s, 1H), 3.80(s, 2H), 3.73-3.57 (m, 2H), yl)methyl]({2-[(9R)-9- 2.64 (s, 1H), 2.21(s, 4H), 2.07 (d, J = 14.1, 1H), (4-fluorophenyl)-6- 1.99 (d, J = 13.9,1H), 1.94-1.64 (m, 4H), 1.64-1.51 (m, oxaspiro[4.5]decan-9- 2H),1.51-1.26 (m, 4H), 1.17 (dd, J = 13.9, 6.3, 1H), yl]ethyl})amine 0.70(dt, J = 13.7, 8.8, 1H). 229 [(3-bromo-5- 466 δ 7.20 (m, 2H), 7.01 (dd,J = 11.1, 6.1, 2H), 6.61 (d, J = 1.1, methylthiophen-2- 1H), 4.01 (s,2H), 3.72 (m, 2H), 2.75 (m, 1H), yl)methyl]({2-[(9R)-9- 2.61 (brs, 1H),2.41 (d, J = 0.9, 3H), 2.32 (m, 1H), (4-fluorophenyl)-6- 2.15 (d, J =14.2, 1H), 2.07 (d, J = 13.9, 1H), 1.99 (m, oxaspiro[4.5]decan-9- 1H),1.89 (m, 2H), 1.77 (m, 1H), 1.67 (ddd, J = 17.0, yl]ethyl})amine 10.6,5.6, 2H), 1.46 (m, 4H), 1.25 (m, 1H), 0.78 (dt, J = 13.9, 8.9, 1H). 230[(5-bromo-4- 466.9 δ 7.20 (d, J = 5.2, 2H), 7.06 (d, J = 8.5, 2H), 6.85(t, J = 3.6, methylthiophen-2- 1H), 3.91 (s, 2H), 3.81-3.62 (m, 2H),2.71 (s, yl)methyl]({2-[(9R)-9- 1H), 2.28 (s, 1H), 2.07 (s, 6H), 1.91(d, J = 13.8, 2H), (4-fluorophenyl)-6- 1.79 (d, J = 10.3, 1H), 1.69(ddd, J = 14.1, 9.4, 4.7, oxaspiro[4.5]decan-9- 2H), 1.59-1.37 (m, 4H),1.28 (s, 1H), 0.80 (dd, J = 8.8, yl]ethyl})amine 4.9, 1H). 231{2-[2,2-diethyl-4-(4- 472.2 δ 7.31 (d, J = 4.9, 2H), 7.07 (dd, J = 8.9,5.2, 2H), fluorophenyl)oxan-4- 6.99 (s, 2H), 6.95 (d, J = 4.5, 2H), 6.89(t, J = 8.6, 2H), yl]ethyl}bis(thiophen- 4.24 (s, 2H), 3.58 (dt, J =23.8, 6.6, 2H), 2.66 (m, 1H), 2-ylmethyl)amine 2.06 (d, J = 14.0, 4H),1.82 (m, 2H), 1.51 (d, J = 14.3, 3H), 1.25 (m, 2H), 0.94 (dd, J = 14.6,7.4, 1H), 0.74 (t, J = 7.5, 4H), 0.42 (t, J = 7.4, 3H). 232 [(4,5- 514.8δ 8.61 (dd, J = 5.3, 1.3, 1H), 8.13 (td, J = 8.0, 1.7,dibromothiophen-2- 1H), 7.64 (d, J = 8.2, 1H), 7.60 (m, 1H), 6.94 (s,1H), yl)methyl]({2-[(9R)-9- 4.40 (brs, 1H), 4.11 (s, 2H), 3.77 (ddd, J =36.9, 13.7, (pyridin-2-yl)-6- 7.2, 2H), 2.98 (td, J = 11.3, 6.0, 1H),2.54 (td, J = 11.2, oxaspiro[4.5]decan-9- 4.3, 1H), 2.38 (m, 1H), 2.22(m, 3H), 1.98 (d, J = 14.0, yl]ethyl})amine 1H), 1.83 (dt, J = 18.5,9.2, 2H), 1.68 (m, 1H), 1.48 (m, 4H), 1.21 (d, J = 37.1, 1H), 0.75 (dt,J = 13.1, 9.0, 1H). 233 [(3,4- 514.8 δ 8.39 (d, J = 4.0, 1H), 7.67 (t, J= 7.0, 1H), 7.38 (s, dibromothiophen-2- 1H), 7.28 (d, J = 8.1, 1H), 7.18(s, 1H), 4.22 (d, J = 18.2, yl)methyl]({2-[(9R)-9- 2H), 3.65 (dd, J =11.2, 7.1, 2H), 3.09-2.85 (m, (pyridin-2-yl)-6- 1H), 2.60 (s, 1H), 2.22(dd, J = 25.9, 13.8, 2H), oxaspiro[4.5]decan-9- 2.10-1.83 (m, 2H),1.87-1.50 (m, 4H), 1.36 (dd, J = 18.7, yl]ethyl})amine 10.7, 3H), 1.02(s, 2H), 0.68-0.50 (m, 1H). 234 [(4,5- 531.8 δ 7.20 (m, 2H), 7.05 (t, J= 8.6, 2H), 6.81 (s, 1H), dibromothiophen-2- 3.91 (s, 2H), 3.74 (m, 2H),3.60 (brs, 1H), 2.74 (m, yl)methyl]({2-[(9R)-9- 1H), 2.31 (td, J = 12.1,4.7, 1H), 2.15 (d, J = 14.1, 1H), (4- 2.08 (d, J = 13.9, 1H), 1.88 (m,4H), 1.67 (ddd, J = 15.1, fluorophenyl)-6- 10.2, 5.0, 2H), 1.46 (ddd, J= 27.4, 14.5, 7.2, oxaspiro[4.5]decan-9- 4H), 1.24 (dd, J = 10.5, 5.6,1H), 0.78 (dt, J = 13.5, yl]ethyl})amine 8.8, 1H). 235 [(3,4- 531.8 δ7.35 (s, 1H), 7.11-7.06 (m, 2H), 6.94 (dd, J = 14.3, dibromothiophen-2-5.7, 2H), 4.05 (s, 2H), 3.75-3.56 (m, 2H), yl)methyl]({2-[(9R)-9- 2.70(dd, J = 11.9, 7.4, 1H), 2.25 (dd, J = 11.7, 7.3, 1H), (4- 2.08 (d, J =14.7, 1H), 1.99 (d, J = 13.9, 1H), fluorophenyl)-6- 1.95-1.65 (m, 4H),1.65-1.50 (m, 2H), 1.50-1.29 (m, oxaspiro[4.5]decan-9- 4H), 1.16 (dd, J= 14.8, 7.3, 1H), 0.70 (dt, J = 13.6, yl]ethyl})amine 8.8, 1H). 236 [(2-369 δ 8.82 (s, 2H), 8.61 (dd, J = 4.8, 1.2, 1H),fluorophenyl)methyl]({2- 7.85 (td, J = 7.8, 1.8, 1H), 7.51 (m, 3H), 7.30(m, 3H), [(9R)-9-(pyridin- 5.22 (s, 2H), 4.12 (d, J = 5.3, 2H), 3.66 (m,2H), 2-yl)-6- 2.90 (d, J = 4.5, 1H), 2.39 (m, 3H), 2.08 (td, J = 12.8,oxaspiro[4.5]decan- 4.4, 1H), 1.54 (m, 7H), 1.02 (dd, J = 12.3,9-yl]ethyl})amine 5.8, 1H), 0.68 (dt, J = 13.3, 8.9, 1H). 237 [(2- 429 δ8.93 (s, 2H), 8.60 (dd, J = 4.8, 1.2, 1H), bromophenyl)methyl]({2- 7.83(td, J = 7.8, 1.9, 1H), 7.71 (dd, J = 8.0, 1.1, 1H), [(9R)-9-(pyridin-7.50 (m, 3H), 7.33 (m, 2H), 4.18 (s, 2H), 3.65 (m, 2-yl)-6- 2H), 2.94(s, 1H), 2.43 (t, J = 12.2, 3H), 2.11 (td, J = 12.8, oxaspiro[4.5]decan-4.4, 1H), 1.89 (m, 2H), 1.55 (m, 7H), 9-yl]ethyl})amine 1.01 (m, 1H),0.67 (dt, J = 13.3, 8.9, 1H). 238 [(2- 385 δ 8.75 (dd, J = 5.4, 1.2,1H), 8.52 (s, 3H), chlorophenyl)methyl]({2- 8.22 (td, J = 8.0, 1.7, 1H),7.77 (d, J = 8.2, 1H), [(9R)-9-(pyridin- 7.67 (ddd, J = 7.5, 5.4, 0.9,1H), 7.42 (m, 4H), 4.20 (d, 2-yl)-6- J = 14.0, 2H), 3.72 (m, 2H), 3.05(td, J = 12.0, oxaspiro[4.5]decan- 5.1, 1H), 2.53 (td, J = 12.0, 4.4,1H), 2.36 (m, 9-yl]ethyl})amine 3H), 2.17 (m, 1H), 2.01 (d, J = 14.2,1H), 1.79 (ddd, J = 9.3, 6.7, 3.4, 2H), 1.52 (m, 5H), 1.17 (m, 1H), 0.78(dt, J = 12.9, 8.8, 1H). 239 [(2- 365.1 δ 8.81 (dd, J = 5.7, 1.3, 1H),8.43 (td, J = 8.0, 1.7, methylphenyl)methyl]({2- 1H), 7.98 (s, 1H), 7.92(d, J = 8.2, 1H), 7.86 (ddd, [(9R)-9-(pyridin- J = 7.6, 5.7, 1.0, 1H),7.27 (m, 2H), 7.18 (m, 2H), 2-yl)-6- 3.98 (s, 2H), 3.75 (m, 2H), 2.98(d, J = 4.4, 1H), oxaspiro[4.5]decan- 2.44 (m, 2H), 2.36 (m, 5H), 2.25(dd, J = 13.5, 9-yl]ethyl})amine 5.4, 1H), 2.07 (d, J = 14.3, 1H), 1.84(m, 2H), 1.55 (m, 5H), 1.23 (m, 1H), 0.83 (dt, J = 13.0, 8.8, 1H). 240{2-[(9R)-9-(pyridin-2- 419.1 δ 8.71 (dd, J = 5.3, 1.2, 1H), 8.18 (td, J= 8.0, 1.7, yl)-6- 1H), 7.79 (d, J = 7.8, 1H), 7.75 (d, J = 8.2, 1H),oxaspiro[4.5]decan- 7.70 (m, 2H), 7.62 (ddd, J = 13.7, 6.8, 1.2, 2H), 9-6.71 (s, 3H), 4.23 (s, 2H), 3.75 (ddd, J = 17.6, 8.8, yl]ethyl}({[2-3.7, 2H), 3.08 (m, 1H), 2.56 (m, 1H), 2.36 (m,(trifluoromethyl)phenyl]methyl})amine 3H), 2.19 (m, 1H), 1.79 (dq, J =7.2, 4.7, 2H), 1.53 (m, 5H), 1.19 (m, 1H), 0.79 (m, 1H). 2412-[({2-[(9R)-9- 367 δ 8.74 (m, 1H), 8.21 (td, J = 8.0, 1.8, 1H),(pyridin-2-yl)-6- 7.75 (d, J = 8.2, 1H), 7.66 (ddd, J = 7.6, 5.4, 1.0,1H), oxaspiro[4.5]decan- 7.27 (m, 1H), 7.20 (dd, J = 7.6, 1.6, 1H), 6.90(m, 9- 4H), 4.05 (s, 2H), 3.72 (ddd, J = 12.4, 11.1, 5.4,yl]ethyl}amino)methyl]phenol 2H), 2.96 (d, J = 5.2, 1H), 2.35 (m, 4H),2.13 (m, 1H), 1.78 (m, 2H), 1.51 (m, 5H), 1.15 (dd, J = 4.0, 2.0, 1H),0.78 (m, 1H). 242 [(2- 381.1 δ 9.66 (s, 3H), 8.80 (dd, J = 5.5, 1.2,1H), methoxyphenyl)methyl]({2- 8.31 (td, J = 8.0, 1.7, 1H), 7.77 (m,3H), 7.42 (ddd, J = 15.9, [(9R)-9- 8.0, 1.6, 1H), 7.25 (dd, J = 7.5,1.6, 1H), (pyridin-2- 7.04 (m, 1H), 6.96 (td, J = 7.5, 1.0, 1H), 4.04(s, yl)-6- 2H), 3.85 (m, 4H), 3.73 (m, 2H), 2.97 (d, J = 4.9,oxaspiro[4.5]decan- 1H), 2.37 (m, 4H), 2.19 (dd, J = 13.2, 5.2, 1H),9-yl]ethyl})amine 2.04 (d, J = 14.1, 1H), 1.81 (ddd, J = 14.0, 9.5, 4.5,2H), 1.81 (ddd, J = 14.0, 9.5, 4.5, 2H), 1.54 (m, 5H), 1.18 (m, 1H),0.80 (m, 1H). 243 [(3- 369 δ 8.77 (dd, J = 5.4, 1.5, 1H), 8.38 (s, 1H),fluorophenyl)methyl]({2- 8.29 (td, J = 8.0, 1.7, 1H), 7.82 (d, J = 8.2,1H), [(9R)-9-(pyridin- 7.74 (dd, J = 7.1, 6.1, 1H), 7.43 (ddd, J = 13.8,7.5, 2-yl)-6- 1.4, 1H), 7.19 (m, 3H), 6.90 (s, 3H), 4.03 (d, J = 2.0,oxaspiro[4.5]decan- 2H), 3.74 (m, 2H), 2.98 (dt, J = 11.4, 5.6,9-yl]ethyl})amine 1H), 2.42 (ddd, J = 29.2, 13.0, 3.8, 4H), 2.18 (m,1H), 2.03 (d, J = 14.1, 1H), 1.81 (ddd, J = 13.9, 9.4, 4.5, 2H), 1.55(m, 5H), 1.20 (ddd, J = 9.9, 6.9, 2.4, 1H), 0.80 (dt, J = 12.9, 8.8,1H). 244 [(3- 431 δ 8.75 (dd, J = 5.4, 1.2, 1H), 8.41 (s, 1H),bromophenyl)methyl]({2- 8.25 (td, J = 8.0, 1.8, 1H), 7.79 (d, J = 8.2,1H), [(9R)-9-(pyridin- 7.70 (ddd, J = 7.6, 5.5, 0.9, 1H), 7.59 (m, 2H),2-yl)-6- 7.36 (ddd, J = 22.8, 10.9, 4.6, 2H), 6.76 (s, 3H),oxaspiro[4.5]decan- 4.01 (d, J = 2.3, 2H), 3.74 (ddd, J = 12.3, 11.0,5.4, 9-yl]ethyl})amine 2H), 2.97 (d, J = 5.0, 1H), 2.38 (m, 4H), 2.16(m, 1H), 2.00 (m, 1H), 1.79 (ddd, J = 8.6, 7.8, 4.7, 2H), 1.53 (m, 5H),1.20 (m, 1H), 0.80 (m, 1H). 245 [(3- 385 δ 8.72 (dd, J = 5.4, 1.1, 1H),8.57 (s, 1H), chlorophenyl)methyl]({2- 8.19 (td, J = 8.0, 1.8, 1H), 7.74(d, J = 8.2, 1H), [(9R)-9-(pyridin- 7.64 (ddd, J = 7.6, 5.4, 0.9, 1H),7.37 (m, 5H), 3.99 (d, 2-yl)-6- J = 2.3, 2H), 3.70 (m, 2H), 2.95 (m,1H), 2.36 (m, oxaspiro[4.5]decan- 4H), 2.12 (td, J = 12.9, 5.1, 1H),1.76 (ddd, J = 14.2, 9-yl]ethyl})amine 9.3, 5.1, 2H), 1.50 (m, 5H), 0.77(dt, J = 13.0, 8.9, 1H). 246 [(3- 365 δ 8.81 (dd, J = 5.7, 1.3, 1H),8.43 (td, J = 8.0, 1.7, methylphenyl)methyl]({2- 1H), 7.98 (s, 1H), 7.92(d, J = 8.2, 1H), 7.86 (ddd, [(9R)-9-(pyridin- J = 7.6, 5.7, 1.0, 1H),7.24 (dq, J = 19.8, 7.4, 4H), 2-yl)-6- 3.98 (s, 2H), 3.75 (m, 2H), 2.98(d, J = 4.4, 1H), oxaspiro[4.5]decan- 2.44 (m, 2H), 2.36 (m, 5H), 2.25(dd, J = 13.5, 9-yl]ethyl})amine 5.4, 1H), 2.07 (d, J = 14.3, 1H), 1.84(m, 2H), 1.55 (m, 5H), 1.23 (m, 1H), 0.83 (dt, J = 13.0, 8.8, 1H). 247methyl 3-[({2-[(9R)-9- 409.1 δ 8.78 (dd, J = 5.5, 1.3, 1H), 8.33 (td, J= 8.0, 1.7, (pyridin-2-yl)-6- 1H), 8.24 (s, 1H), 8.04 (m, 2H), 7.85 (d,J = 8.2, oxaspiro[4.5]decan- 1H), 7.78 (m, 1H), 7.63 (m, 2H), 7.55 (d, J= 7.7, 9- 1H), 4.10 (d, J = 2.0, 2H), 3.90 (s, 3H), 3.75 (ddd,yl]ethyl}amino)methyl]benzoate J = 12.2, 11.0, 5.4, 2H), 3.00 (dd, J =11.5, 7.1, 1H), 2.40 (m, 4H), 2.21 (m, 1H), 2.04 (d, J = 14.2, 1H), 1.83(ddd, J = 13.9, 9.2, 4.3, 2H), 1.51 (dddd, J = 17.6, 10.1, 8.1, 3.0,5H); 1.21 (s, 1H), 0.82 (dd, J = 15.6, 6.6, 1H). 248 3-[({2-[(9R)-9- 367δ 8.77 (dd, J = 5.5, 1.2, 1H), 8.30 (td, J = 8.0, 1.7, (pyridin-2-yl)-6-1H), 7.81 (s, 1H), 7.75 (ddd, J = 7.6, 5.5, 1.0, 1H),oxaspiro[4.5]decan- 7.23 (t, J = 8.1, 1H), 6.85 (dt, J = 3.2, 2.1, 3H),9- 6.65 (s, 3H), 3.96 (s, 2H), 3.73 (dd, J = 13.8, 7.3,yl]ethyl}amino)methyl]phenol 2H), 2.96 (s, 1H), 2.36 (m, 4H), 2.15 (ddd,J = 9.9, 8.5, 4.7, 1H), 2.03 (d, J = 14.2, 1H), 1.80 (dt, J = 11.2, 4.8,2H), 1.52 (ddd, J = 21.7, 12.8, 7.4, 5H), 1.20 (m, 1H), 0.80 (d, J =13.3, 1H). 249 {2-[(9R)-9-(pyridin-2- 419.1 δ 8.66 (m, 1H), 8.07 (td, J= 7.9, 1.8, 1H), yl)-6- 7.72 (m, 2H), 7.65 (m, 2H), 7.54 (m, 2H), 6.22(s, 2H), oxaspiro[4.5]decan- 4.08 (d, J = 3.1, 2H), 3.71 (m, 2H), 2.97(d, J = 5.0, 9- 1H), 2.34 (dddd, J = 25.4, 19.6, 16.7, 4.4,yl]ethyl}({[3- 4H), 2.09 (m, 1H), 1.74 (m, 2H), 1.49 (m, 5H),(trifluoromethyl)phenyl]methyl})amine 0.76 (m, 1H). 250 N-methyl-5-[({2-414.1 δ 8.78 (dd, J = 5.6, 1.3, 1H), 8.36 (td, J = 8.0, 1.7,[(9R)-9-(pyridin-2-yl)- 1H), 7.86 (d, J = 8.2, 1H), 7.79 (ddd, J = 7.6,5.6, 6- 1.0, 1H), 7.38 (d, J = 3.8, 1H), 7.14 (d, J = 3.8,oxaspiro[4.5]decan- 1H), 7.06 (d, J = 3.9, 1H), 4.21 (s, 2H), 3.72 (m,9- 2H), 2.97 (td, J = 12.0, 5.1, 1H), 2.84 (d, J = 4.7,yl]ethyl}amino)methyl]thiophene- 3H), 2.34 (m, 4H), 2.16 (m, 1H), 2.03(d, J = 14.2, 2- 1H), 1.80 (dd, J = 12.2, 3.0, 2H), 1.50 (m, 5H),carboxamide 1.20 (m, 1H), 0.82 (s, 1H). 251 N-ethyl-5-[({2-[(9R)- 428.1δ 8.78 (dd, J = 5.6, 1.2, 1H), 8.35 (td, J = 8.0, 1.7,9-(pyridin-2-yl)-6- 1H), 7.86 (d, J = 8.2, 1H), 7.79 (ddd, J = 7.6, 5.6,oxaspiro[4.5]decan- 0.9, 1H), 7.40 (d, J = 3.8, 1H), 7.14 (t, J = 10.7,9- 2H), 6.20 (s, 4H), 4.21 (d, J = 1.2, 2H), 3.72 (m,yl]ethyl}amino)methyl]thiophene- 2H), 3.34 (m, 2H), 2.97 (m, 1H), 2.39(m, 4H), 2- 2.18 (m, 1H), 2.03 (d, J = 14.2, 1H), 1.81 (m, 2H),carboxamide 1.52 (m, 5H), 1.19 (m, 4H), 0.80 (m, 1H). 252N-methyl-3-[({2- 408.1 δ 8.75 (dd, J = 5.4, 1.2, 1H), 8.24 (td, J = 8.0,1.7, [(9R)-9-(pyridin-2-yl)- 1H), 7.89 (s, 1H), 7.77 (m, 2H), 7.69 (ddd,J = 7.6, 6- 5.5, 0.9, 1H), 7.49 (ddd, J = 18.3, 10.6, 4.6,oxaspiro[4.5]decan- 2H), 7.33 (s, 1H), 4.07 (s, 2H), 3.73 (m, 2H), 9-2.98 (m, 1H), 2.88 (d, J = 4.6, 3H), 2.47 (t, J = 10.7,yl]ethyl}amino)methyl]benzamide 1H), 2.36 (dd, J = 12.8, 7.5, 3H), 2.16(d, J = 4.8, 1H), 1.79 (m, 2H), 1.50 (ddd, J = 18.7, 13.3, 6.9, 5H),1.19 (ddd, J = 8.3, 7.0, 1.8, 1H), 0.80 (d, J = 13.3, 1H). 253N-ethyl-3-[({2-[(9R)- 422.1 δ 8.70 (dd, J = 5.3, 1.2, 1H), 8.43 (s, 1H),9-(pyridin-2-yl)-6- 8.14 (td, J = 7.9, 1.8, 1H), 7.89 (d, J = 1.4, 1H),oxaspiro[4.5]decan- 7.76 (dt, J = 7.3, 1.6, 1H), 7.71 (d, J = 8.2, 1H),9- 7.59 (ddd, J = 7.6, 5.3, 0.9, 1H), 7.46 (m, 2H), 7.37 (s,yl]ethyl}amino)methyl]benzamide 1H), 6.55 (s, 3H), 4.05 (s, 2H), 3.70(m, 2H), 3.36 (qd, J = 7.2, 5.7, 2H), 2.96 (d, J = 7.9, 1H), 2.45 (t, J= 10.2, 1H), 2.32 (dd, J = 21.2, 8.7, 3H), 2.11 (d, J = 5.2, 1H), 1.77(m, 2H), 1.47 (m, 5H), 1.19 (m, 4H), 0.76 (d, J = 13.3, 1H). 254 [(4-381.1 δ 9.09 (d, J = 86.1, 2H), 8.69 (d, J = 5.0, 1H),methoxyphenyl)methyl]({2- 8.29 (t, J = 7.7, 1H), 8.06 (s, 3H), 7.75 (m,2H), [(9R)-9- 7.20 (d, J = 8.6, 2H), 6.81 (d, J = 8.6, 2H), 3.89 (s,(pyridin-2- 2H), 3.79 (m, 4H), 3.66 (m, 1H), 2.96 (s, 1H), yl)-6- 2.43(dd, J = 23.4, 11.5, 2H), 2.27 (t, J = 16.0, oxaspiro[4.5]decan- 3H),2.01 (d, J = 14.2, 1H), 1.83 (dd, J = 19.3, 9.5, 9-yl]ethyl})amine 2H),1.66 (m, 1H), 1.47 (m, 4H), 1.14 (d, J = 7.0, 1H), 0.75 (m, 1H). 2554-[({2-[(9R)-9- 367 δ 8.76 (dd, J = 5.5, 1.2, 1H), 8.26 (m, 1H),(pyridin-2-yl)-6- 7.80 (d, J = 8.2, 1H), 7.72 (ddd, J = 7.6, 5.5, 0.9,1H), oxaspiro[4.5]decan- 7.65 (s, 1H), 7.22 (m, 2H), 6.82 (m, 2H), 3.93(s, 9- 2H), 3.73 (dd, J = 10.7, 7.6, 2H), 2.94 (dd, J = 11.1,yl]ethyl}amino)methyl]phenol 5.9, 1H), 2.36 (m, 4H), 2.13 (m, 1H), 2.01(m, 1H), 1.80 (d, J = 3.6, 2H), 1.51 (dd, J = 9.7, 5.6, 5H), 1.19 (m,1H), 0.81 (s, 1H). 256 [(2,3- 387 δ 8.75 (dd, J = 5.4, 1.3, 1H), 8.26(td, J = 8.0, 1.7, difluorophenyl)methyl]({2- 1H), 7.80 (d, J = 8.2,1H), 7.71 (ddd, J = 7.5, 5.5, [(9R)-9- 0.9, 1H), 7.34 (dtd, J = 10.0,7.9, 1.9, 1H), (pyridin-2- 7.21 (m, 4H), 4.11 (s, 2H), 3.72 (m, 2H),3.02 (td, J = 12.0, yl)-6- 5.1, 1H), 2.49 (td, J = 12.1, 4.3, 1H),oxaspiro[4.5]decan- 2.35 (m, 3H), 2.16 (m, 1H), 2.01 (d, J = 14.1, 1H),9-yl]ethyl})amine 1.79 (ddd, J = 11.2, 9.4, 4.1, 2H), 1.52 (m, 5H), 1.17(m, 1H), 0.78 (dt, J = 12.9, 8.8, 1H). 257 [(2,4- 387 δ 8.79 (dd, J =5.5, 1.3, 1H), 8.38 (s, 1H), difluorophenyl)methyl]({2- 8.32 (m, 1H),7.84 (d, J = 8.2, 1H), 7.76 (ddd, J = 7.6, [(9R)-9- 5.5, 0.9, 1H), 7.50(dd, J = 14.8, 8.3, 1H), (pyridin-2- 7.03 (m, 2H), 4.08 (s, 2H), 3.74(m, 2H), 3.02 (td, J = 12.0, yl)-6- 5.0, 1H), 2.42 (m, 4H), 2.18 (m,1H), oxaspiro[4.5]decan- 2.03 (d, J = 14.2, 1H), 1.82 (ddd, J = 14.2,9.6, 4.5, 9-yl]ethyl})amine 2H), 1.56 (m, 5H), 1.19 (ddd, J = 7.0, 6.2,2.8, 1H), 0.80 (dt, J = 12.9, 8.8, 1H). 258 [(2,5- 387 δ 8.74 (dd, J =5.4, 1.2, 1H), 8.26 (td, J = 8.0, 1.7, difluorophenyl)methyl]({2- 1H),7.72 (m, 2H), 7.21 (dddd, J = 8.4, 7.0, 4.8, [(9R)-9- 1.8, 3H), 6.45 (s,3H), 4.07 (s, 2H), 3.73 (ddd, J = 12.2, (pyridin-2- 11.1, 5.5, 2H), 3.02(d, J = 5.2, 1H), 2.49 (d, yl)-6- J = 4.3, 1H), 2.36 (dt, J = 11.8, 4.5,3H), 2.18 (dd, oxaspiro[4.5]decan- J = 12.3, 5.2, 1H), 2.00 (m, 1H),1.79 (ddd, J = 13.9, 9-yl]ethyl})amine 9.3, 4.4, 2H), 1.49 (m, 5H), 1.18(m, 1H), 0.78 (d, J = 13.3, 1H). 259 [(2,6- 387.1 δ 8.79 (dd, J = 5.6,1.3, 1H), 8.36 (m, 1H), difluorophenyl)methyl]({2- 8.20 (s, 4H), 7.86(d, J = 8.2, 1H), 7.79 (ddd, J = 7.6, [(9R)-9- 5.6, 1.0, 1H), 7.50 (tt,J = 8.5, 6.6, 1H), 7.04 (m, (pyridin-2- 2H), 4.13 (s, 2H), 3.72 (m, 2H),3.05 (td, J = 12.0, yl)-6- 5.1, 1H), 2.52 (td, J = 12.1, 4.2, 1H), 2.37(m, oxaspiro[4.5]decan- 3H), 2.19 (m, 1H), 2.04 (d, J = 14.2, 1H), 1.81(m, 9-yl]ethyl})amine 2H), 1.53 (m, 5H), 1.18 (m, 1H), 0.79 (dt, J =12.8, 8.8, 1H). 260 [(3,4- 387.1 δ 8.84 (s, 1H), 8.79 (dd, J = 5.6, 1.3,1H), difluorophenyl)methyl]({2- 8.41 (td, J = 8.0, 1.6, 1H), 8.25 (s,1H), 7.86 (ddd, J = 13.3, [(9R)-9- 7.6, 7.0, 2H), 7.30 (m, 3H), 3.99 (d,J = 1.7, (pyridin-2- 2H), 3.73 (m, 2H), 2.96 (dd, J = 12.1, 7.4, 1H),yl)-6- 2.38 (m, 4H), 2.21 (m, 1H), 2.05 (d, J = 14.2, 1H),oxaspiro[4.5]decan- 1.82 (ddd, J = 12.6, 9.0, 4.2, 2H), 1.53 (m, 5H),9-yl]ethyl})amine 1.21 (m, 1H), 0.81 (dt, J = 12.9, 8.8, 1H). 261 [(3,5-387 δ 8.77 (d, J = 5.4, 1H), 8.43 (s, 1H), 8.35 (d, J = 7.7,difluorophenyl)methyl]({2- 1H), 7.83 (m, 2H), 7.03 (m, 3H), 4.01 (s,2H), [(9R)-9- 3.74 (ddd, J = 27.7, 13.8, 7.4, 2H), 2.96 (m, 1H),(pyridin-2- 2.39 (m, 4H), 2.23 (dd, J = 13.3, 5.1, 1H), yl)-6- 2.02 (m,1H), 1.81 (m, 2H), 1.52 (m, 5H), 1.21 (dd, J = 9.4, oxaspiro[4.5]decan-5.3, 1H), 0.80 (dt, J = 12.9, 8.9, 1H). 9-yl]ethyl})amine 262 [(2,3-411.1 δ 8.75 (dd, J = 5.4, 1.2, 1H), 8.21 (td, J = 8.0, 1.8,dimethoxyphenyl)methyl]({2- 1H), 7.88 (s, 2H), 7.75 (d, J = 8.2, 1H),7.66 (ddd, [(9R)-9- J = 7.6, 5.4, 0.9, 1H), 7.08 (dd, J = 9.0, 5.6, 2H),(pyridin-2- 6.87 (dd, J = 6.2, 3.0, 1H), 4.05 (s, 2H), 3.86 (d, J = 6.3,yl)-6- 6H), 3.73 (ddd, J = 12.5, 11.1, 5.4, 2H), oxaspiro[4.5]decan-2.97 (s, 1H), 2.45 (s, 1H), 2.35 (m, 3H), 2.14 (m, 9-yl]ethyl})amine1H), 1.78 (ddd, J = 14.2, 6.0, 3.9, 2H), 1.49 (m, 5H), 1.16 (m, 1H),0.77 (d, J = 13.3, 1H). 263 [(3,4- 411.1 δ 8.73 (dd, J = 5.5, 1.2, 1H),8.24 (td, J = 8.0, 1.7, dimethoxyphenyl)methyl]({2- 1H), 8.00 (s, 1H),7.78 (d, J = 8.2, 1H), 7.69 (ddd, [(9R)-9- J = 7.5, 5.5, 0.8, 1H), 6.96(d, J = 1.0, 1H), (pyridin-2- 6.88 (d, J = 1.7, 2H), 6.55 (s, 3H), 3.93(s, 2H), 3.78 (t, yl)-6- J = 7.5, 6H), 3.72 (m, 2H), 2.92 (s, 1H), 2.35(m, oxaspiro[4.5]decan- 4H), 2.15 (m, 1H), 1.99 (d, J = 14.2, 1H), 1.79(m, 9-yl]ethyl})amine 2H), 1.49 (m, 5H), 1.18 (s, 1H), 0.79 (dd, J =15.6, 6.6, 1H). 264 2-methoxy-4-[({2- 397.1 δ 8.62 (dd, J = 5.0, 1.0,1H), 7.94 (td, J = 7.9, 1.8, [(9R)-9-(pyridin-2-yl)- 1H), 7.57 (d, J =8.1, 1H), 7.42 (m, 1H), 7.00 (s, 6- 1H), 6.81 (d, J = 0.8, 2H), 3.93 (s,2H), 3.84 (s, oxaspiro[4.5]decan- 3H), 3.70 (m, 3H), 2.93 (s, 1H), 2.36(s, 3H), 9- 2.17 (m, 1H), 1.90 (d, J = 13.7, 1H), 1.74 (m, 2H),yl]ethyl}amino)methyl]phenol 1.51 (s, 5H), 1.13 (m, 1H), 0.73 (dt, J =13.2, 8.9, 1H). 265 [(5-fluoropyridin-3- 370 δ 8.82 (s, 1H), 8.50 (dd, J= 34.5, 26.7, 3H), yl)methyl]({2-[(9R)-9- 7.93 (m, 2H), 7.74 (t, J =9.7, 1H), 4.12 (d, J = 10.8, (pyridin-2- 2H), 3.76 (dd, J = 25.7, 11.8,2H), 3.03 (d, J = 7.9, yl)-6- 1H), 2.39 (m, 5H), 2.09 (t, J = 13.0, 1H),1.85 (d, oxaspiro[4.5]decan- J = 9.0, 2H), 1.60 (d, J = 44.8, 5H), 1.24(s, 1H), 9-yl]ethyl})amine 0.86 (d, J = 9.1, 1H). 266[(5-bromopyridin-3- 430 δ 8.64 (m, 5H), 8.16 (s, 1H), 8.00 (d, J = 8.2,1H), yl)methyl]({2-[(9R)-9- 7.95 (m, 1H), 4.10 (m, 2H), 3.76 (m, 2H),(pyridin-2- 3.02 (td, J = 12.4, 5.0, 1H), 2.49 (m, 2H), 2.29 (m, yl)-6-3H), 2.12 (t, J = 10.2, 1H), 1.88 (ddd, J = 25.8, oxaspiro[4.5]decan-12.8, 8.1, 2H), 1.57 (m, 5H), 1.26 (m, 1H), 9-yl]ethyl})amine 0.86 (dt,J = 12.9, 8.9, 1H). 267 [(5-chloropyridin-3- 386 δ 8.80 (s, 1H), 8.63(s, 1H), 8.49 (dd, J = 17.4, yl)methyl]({2-[(9R)-9- 10.6, 3H), 7.93 (m,3H), 4.08 (s, 2H), 3.75 (dd, J = 29.6, (pyridin-2- 6.9, 2H), 2.99 (d, J= 11.6, 1H), 2.45 (m, yl)-6- 2H), 2.28 (m, 3H), 2.08 (d, J = 14.3, 1H),1.85 (d, oxaspiro[4.5]decan- J = 7.5, 2H), 1.60 (m, 5H), 1.23 (s, 1H),0.84 (d, J = 5.6, 9-yl]ethyl})amine 1H). 268 [(5-methoxypyridin- 382.1 δ8.81 (d, J = 5.5, 1H), 8.48 (m, 3H), 7.95 (m, 3-yl)methyl]({2-[(9R)-3H), 4.22 (d, J = 13.4, 2H), 3.98 (s, 3H), 9- 3.75 (ddd, J = 19.2, 12.7,9.3, 2H), 3.04 (td, J = 11.6, (pyridin-2-yl)-6- 4.8, 1H), 2.42 (m, 7H),2.09 (d, J = 14.3, 1H), oxaspiro[4.5]decan- 1.88 (m, 2H), 1.57 (m, 6H),1.26 (d, J = 10.9, 1H), 9- 0.85 (dt, J = 12.4, 8.7, 1H). yl]ethyl})amine269 5-[({2-[(9R)-9- 377.1 δ 8.96 (d, J = 15.0, 1H), 8.83 (t, J = 10.5,2H), (pyridin-2-yl)-6- 8.53 (dt, J = 15.9, 8.0, 2H), 8.23 (d, J = 15.0,1H), oxaspiro[4.5]decan- 7.97 (ddd, J = 13.4, 11.9, 7.5, 2H), 4.13 (m,2H), 9- 3.77 (m, 2H), 3.02 (m, 1H), 2.50 (ddd, J = 26.3,yl]ethyl}amino)methyl]pyridine- 14.4, 3.7, 2H), 2.31 (m, 3H), 2.13 (dd,J = 19.3, 3- 11.3, 1H), 1.88 (ddd, J = 17.2, 11.0, 7.0, 2H),carbonitrile 1.58 (m, 5H), 1.27 (m, 1H), 0.85 (dt, J = 12.8, 8.7, 1H).270 [(5-methylpyridin-3- 366 δ 8.71 (dd, J = 50.6, 19.3, 3H), 8.37 (m,2H), yl)methyl]({2-[(9R)-9- 7.85 (m, 2H), 4.20 (d, J = 13.3, 2H), 3.74(ddd, J = 11.9, (pyridin-2- 11.1, 5.6, 2H), 3.02 (m, 1H), 2.44 (m, 7H),yl)-6- 2.25 (dd, J = 12.5, 5.0, 1H), 1.84 (m, 2H), oxaspiro[4.5]decan-1.57 (tdd, J = 24.6, 15.7, 8.5, 5H), 1.22 (d, J = 9.3, 9-yl]ethyl})amine1H), 0.83 (m, 1H). 271 {2-[(9R)-9-(pyridin-2- 420.1 δ 8.96 (s, 1H), 8.81(m, 2H), 8.45 (td, J = 8.1, 1.6, yl)-6- 2H), 8.21 (s, 1H), 7.90 (m, 2H),4.16 (m, 2H), oxaspiro[4.5]decan- 3.77 (dtd, J = 12.7, 9.5, 5.3, 2H),3.04 (td, J = 12.2, 9- 5.1, 1H), 2.50 (m, 2H), 2.31 (ddd, J = 21.7,yl]ethyl}({[5- 14.1, 7.0, 3H), 2.12 (d, J = 12.6, 1H), 1.87 (ddd, J =20.7, (trifluoromethyl)pyridin- 12.7, 7.7, 2H), 1.58 (m, 5H), 1.26 (m,3- 1H), 0.85 (m, 1H). yl]methyl})amine 272 {[6-chloro-5- 454.1 δ 8.70(m, 1H), 8.60 (d, J = 2.1, 1H), 8.28 (d, J = 2.2,(trifluoromethyl)pyridin- 1H), 8.16 (td, J = 7.9, 1.8, 1H), 7.73 (d, J =8.2, 3- 1H), 7.62 (ddd, J = 7.6, 5.3, 1.0, 1H), yl]methyl}({2-[(9R)-9-4.12 (m, 2H), 3.73 (m, 2H), 3.18 (brs, 1H), 2.99 (td, J = 12.0,(pyridin-2-yl)-6- 5.1, 2H), 2.49 (td, J = 12.0, 4.4, 1H),oxaspiro[4.5]decan- 2.35 (dd, J = 14.1, 1.9, 3H), 2.13 (ddd, J = 14.2,12.1, 9-yl]ethyl})amine 5.2, 1H), 1.79 (dd, J = 5.6, 3.7, 2H), 1.62 (dd,J = 7.8, 2.8, 1H), 1.51 (dd, J = 7.9, 4.1, 4H), 1.18 (m, 1H), 0.78 (dt,J = 13.2, 8.9, 1H). 273 {[2-fluoro-5- 438.1 δ 8.73 (dd, J = 5.3, 1.2,1H), 8.62 (s, 1H), (trifluoromethyl)pyridin- 8.35 (dd, J = 8.5, 2.3,1H), 8.22 (td, J = 8.0, 1.6, 1H), 3- 7.78 (d, J = 8.2, 1H), 7.67 (dd, J= 6.9, 5.8, 1H), yl]methyl}({2-[(9R)-9- 4.25 (brs, 1H), 4.13 (m, 2H),3.74 (ddd, J = 12.3, (pyridin-2-yl)-6- 11.0, 5.5, 2H), 3.05 (td, J =11.9, 5.1, 1H), oxaspiro[4.5]decan- 2.54 (td, J = 12.0, 4.4, 1H), 2.35(dt, J = 9.7, 5.3, 3H), 9-yl]ethyl})amine 2.16 (ddd, J = 9.9, 8.8, 3.8,1H), 2.01 (d, J = 14.1, 1H), 1.80 (m, 2H), 1.62 (m, 1H), 1.49 (m, 4H),1.19 (m, 1H), 0.79 (dt, J = 13.1, 8.8, 1H). 274 {[6-fluoro-5- 438.1 δ8.58 (d, J = 4.0, 1H), 8.45 (s, 1H), 8.35 (d, J = 9.0,(trifluoromethyl)pyridin- 1H), 7.85 (m, 1H), 7.51 (d, J = 8.1, 1H), 3-7.33 (dd, J = 7.4, 4.9, 1H), 4.12 (m, 2H), 3.70 (dd, J = 8.8,yl]methyl}({2-[(9R)-9- 2.9, 2H), 2.98 (m, 2H), 2.47 (dd, J = 12.1,(pyridin-2-yl)-6- 7.4, 2H), 2.38 (t, J = 11.7, 2H), 2.18 (dd, J = 12.9,oxaspiro[4.5]decan- 4.8, 1H), 1.90 (d, J = 13.7, 1H), 1.70 (m, 2H),9-yl]ethyl})amine 1.60 (m, 1H), 1.50 (dt, J = 39.4, 20.7, 4H), 1.11 (m,1H), 0.73 (dt, J = 13.5, 9.1, 1H). 275 {2-[(9R)-9-(pyridin-2- 420.1 δ9.29 (brs, 1H), 8.90 (s, 1H), 8.86 (d, J = 5.1, yl)-6- 1H), 8.80 (dd, J= 5.7, 1.2, 1H), 8.49 (td, J = 8.0, oxaspiro[4.5]decan- 1.7, 1H), 7.98(d, J = 8.2, 1H), 7.91 (ddd, J = 7.6, 9- 5.7, 1.0, 1H), 7.74 (d, J =5.1, 1H), 4.27 (m, 2H), yl]ethyl}({[3- 3.81 (dt, J = 12.8, 4.6, 1H),3.72 (m, 1H), (trifluoromethyl)pyridin- 3.13 (td, J = 12.1, 5.1, 1H),2.60 (td, J = 12.3, 4.1, 1H), 2- 2.49 (m, 1H), 2.33 (m, 3H), 2.10 (d, J= 14.3, 1H), yl]methyl})amine 1.85 (m, 2H), 1.65 (m, 1H), 1.52 (m, 4H),1.25 (m, 1H), 0.84 (dt, J = 12.8, 8.8, 1H). 276 {2-[(9R)-9-(pyridin-2-420.1 δ 8.81 (dd, J = 5.5, 1.2, 1H), 8.75 (d, J = 4.4, 1H), yl)-6- 8.32(td, J = 8.0, 1.7, 1H), 8.16 (dd, J = 8.0, 0.7, oxaspiro[4.5]decan- 1H),7.86 (d, J = 8.2, 1H), 7.77 (ddd, J = 7.6, 5.5, 9- 1.0, 1H), 7.59 (dd, J= 7.5, 5.0, 1H), 4.40 (m, 2H), yl]ethyl}({[4- 3.75 (m, 2H), 3.13 (td, J= 12.0, 5.3, 1H), (trifluoromethyl)pyridin- 2.66 (td, J = 12.1, 4.5,1H), 2.49 (ddd, J = 13.7, 11.9, 3- 4.5, 1H), 2.41 (m, 1H), 2.32 (m, 2H),2.07 (d, J = 14.0, yl]methyl})amine 1H), 1.85 (ddd, J = 9.3, 7.7, 4.5,2H), 1.64 (m, 1H), 1.51 (m, 4H), 1.22 (m, 1H), 0.82 (dt, J = 13.1, 8.9,1H). 277 {2-[(9R)-9-(pyridin-2- 420.1 δ 8.80 (dd, J = 5.5, 1.3, 1H),8.75 (d, J = 5.0, 1H), yl)-6- 8.31 (td, J = 8.0, 1.7, 1H), 7.84 (d, J =8.2, 1H), oxaspiro[4.5]decan- 7.75 (ddd, J = 7.6, 5.5, 0.9, 1H), 7.65(M, 2H), 9- 4.31 (m, 2H), 3.74 (m, 2H), 3.09 (td, J = 12.0,yl]ethyl}({[4- 5.2, 1H), 2.60 (td, J = 12.1, 4.4, 1H), 2.36 (m,(trifluoromethyl)pyridin- 4H), 2.05 (d, J = 14.1, 1H), 1.82 (m, 2H),1.64 (m, 2- 1H), 1.50 (m, 4H), 1.20 (m, 1H), 0.81 (dt, J = 12.8,yl]methyl})amine 8.8, 1H). 500 [(4- chlorophenyl)methyl]({2- [4-(4-methoxyphenyl)- 2,2-dimethyloxan-4- yl]ethyl})amine 501 [(3,4-dimethoxyphenyl)methyl][2- (2,2-dimethyl-4- phenyloxan-4- yl)ethyl]amine502 2-[({2-[2-ethyl-2- methyl-4-(4- methylphenyl)oxan-4-yl]ethyl}amino)methyl]phenol 503 [2-(2,2-dimethyl-4- phenyloxan-4-yl)ethyl][(2- fluorophenyl)methyl]amine 504 4-[({2-[4-(2-methoxyphenyl)-2,2- dimethyloxan-4- yl]ethyl}amino)methyl]-N,N-dimethylaniline 505 2-[({2-[2-ethyl-4-(4- fluorophenyl)-2-methyloxan-4- yl]ethyl}amino)methyl] phenol

Example 13 Opioid Receptor Ligands

The following compounds in Table 2 can also be prepared according to theprocedures described above from appropriate starting materials andappropriate reagents and would be expected to also have similarproperties and therapeutic effects as other compounds described herein.In addition to the specific structure shown the other isomers orenantiomers are included with the description herein. Compounds thathave been made lists NMR data and prophetic examples do not list NMRdata.

TABLE 2 Examples with chemical name and/or characterization dataCompound Name Structure and/or NMR Spectrum 506{2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}(pyrimidin-5-ylmethyl)amine ¹H NMR (400 MHz, CD3CN) δ 9.16 (s,IH), 8.78 (s, 2H), 8.70 (dd, J = 5.3, 1.1, 1H), 8.16 (td, J = 8.0, 1.8,1H), 7.74 (d, J 8.2, 1H), 7.62 (ddd, J = 7.6, 5.4, 0.9, 1H), 4.27 (brs,1H), 4.04 (t, J = 7.7, 2H), 3.73 (m, 2H), 3.01 (td, J = 12.0, 5.1, 1H),2.50 (td, J = 12.0, 4.4, 1H), 2.33 (m, 3H), 2.12 (ddd, J = 19.0, 11.7,5.2, 1H), 1.99 (d, J = 10.1, 1H), 1.78 (m, 2H), 1.61 (m, 1H), 1.48 (m,4H), 1.17 (m, 1H), 0.78 (dt, J = 13.1, 8.9, 1H).  

507. [(2-methylpyrimidin-5-yl)methyl]({2-[(9R)-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

508. {2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}({[2-(trifluoromethyl)pyrimidin-5- yl]methyl})amine

509. [(2-methoxypyrimidin-5-yl)methyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine MS: 383.3 ¹H NMR(400 MHz, CD3CN) δ 8.69 (dd, J = 5.2, 1.1, 1H), 8.54 (s, 2H), 8.10 (td,J = 7.9, 1.7, 1H), 7.69 (d, J = 8.1, 1H), 7.56 (dd, J = 6.7, 5.3, 1H),3.98 (s, 5H), 3.71 (m, 3H), 3.50 (brs, 1H), 2.98 (td, J = 12.0, 5.0,1H), 2.47 (td, J = 12.0,4.3, 1H), 2.37 (m, 2H), 2.27 (m, 1H), 2.10 (m,1H), 1.77 (m, 2H), 1.62 (m, 1H), 1.47 (dddd, J = 14.1, 12.4, 8.4, 4.9,4H), 1.17 (m, 1H), 0.77 (dt, J = 13.1, 8.9, 1H).  

510. (pyridazin-4-ylmethyl)({2-[(9R)-9-(pyridin- 2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine

511. [(6-methylpyridazin-4-yI)methyl]({2-[(9R)- 9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

512. {2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}({[6-(trifluoromethyl)pyridazin-4- yl]methyl})amine

513. [(6-methoxypyridazin-4-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan- 9-yl]ethyl})amine

514. (pyrazin-2-ylmethyl)({2-[(9R)-9-(pyridin-2- yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine MS: 353.3 ¹H NMR (400 MHz, CD3CN) δ8.74 (dd, J = 5.3, 1.1, 1H) 8.60 (d J = 1.6, 2H), 8.55 (m, 1H), 8.16(td, J = 7.9, 1.7, 1H), 7.73 (d, . = 8.2, 1H), 7.61 (ddd, J = 7.5, 5.3,0.8, 1H), 7.13 (brs, 1H), 4.25 (m, 2H), 3.73 (m, 2H), 3.09 (td, J =11.8, 5.4, 1H), 2.61 (td, J = 11.9, 4.6, 1H), 2.37 (m, 3H), 2.18 (ddd, J= 13.7, 11.6,5.5, 1H), 1.99 (m, 1H), 1.77 (dd, J = 9.6, 4.4, 2H), 1.62(m, 1H), 1.48 (m, 4H), 1.18 (m, 1H), 0.79 (dt, J = 13.1, 8.9, 1H).  

515. [(6-methylpyrazin-2-yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine

516. {2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}({[6-(trifluoromethyl)pyrazin-2- yl]methyl})amine

517. [(6-methoxypyrazin-2-yl)methyl]({2-[(9R)- 9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

518. [(5-methylpyrazin-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

519. {2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}({[5-(trifluoromethyl)pyrazin-2- yl]methyl})amine

520. [(5-methoxypyrazin-2-yl)methyl]({2-[(9R)-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

521. {2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5}decan-9-yl]ethyl}(quinolin-3-ylmethyl)amine MS: 402.3 ¹H NMR (400 MHz, CD3CN) δ9.90 (brs, IH), 9.15 (d, J = 1.7 1H) 8.89 (s 1H), 8.77 (dd J = 5.6, 1.3,1H), 8.40 (td, = 8.0, 1.6, 1H), 8.30 (d, J = 8.6, 1H), 8.16 (d, J = 8.2,1H), 8.08 (ddd, J = 8.5, 7.0, 1.3, 1H), 7.90 (m, 2H), 7.81 (m, 1H), 4.36(m, 2H), 3.74 (m, 2H), 3.06 (td, J = 12.0, 5.1, 1H), 2.57 (td, J = 12.2,4.1, 1H), 2.45 (m, 1H), 2.29 (m, 3H), 2.08 (m, 1H), 1.98 (d, J = 2.5,1H), 1.83 (m, 2H), 1.64 (ddd, J = 11.6, 8.7, 3.4, 1H), 1.50 (m, 4H),1.23 (ddd, J = 10.4, 4.4, 2.4, 1H), 0.82 (dt, J = 12.9, 8.8, 1H).  

522. (1H-pyrazol-3-ylmethyl)({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine MS: 341.2 1H NMR (400 MHz, CD3CN) δ8.76 (dd, J = 5.5, 1.2 IH) 8.28 (td J = 8.0, 1.7, 1H), 7.80 (d, J = 8.2,1H), 7.73 (ddd, = 7.6, 5.5, 0.9, 1H), 7.61 (d, J = 2.3, 1H), 6.32 (d, J= 2.3, 1H), 5.78 (brs, 1H), 4.09 (m, 2H), 3.72 (m, 2H), 2.98 (td, J =12.0, 5.2, 1H), 2.47 (td, J = 12.1, 4.3, 1H), 2.36 (m, 3H), 2.16 (m,1H), 2.02 (d, J = 14.2, 1H), 1.79 (m, 2H), 1.62 (m, 1H), 1.49 (m, 4H),1.19 (m, 1H), 0.79 (dt, J = 12.9, 8.8, 1H).  

523. [(1-methyl-1H-pyrazol-3-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5ldecan- 9-yl]ethyl})amine MS: 355.31H NMR (400 MHz, CD3CN) δ 8.98 (brs, 1H), 8.73 (dd, J = 5.3, 1.1, 1H),8.73 (dd, J = 5.3, 1.1, 1H), 8.16 (m, 2H), 7.72 (d, J = 8.2, 1H), 7.72(d, J = 8.2, 1H), 7.62 (ddd, J = 7.5, 5.4, 0.8, 1H), 7.62 (ddd, J = 7.5,5.4, 0.8, 1H), 7.47 (d, J = 2.2, 1H), 7.47 (d, J = 2.2, 1H), 6.25 (d, J= 2.2, 1H), 6.25 (d, J = 2.2, 1H), 4.02 (m, 2H), 3.80 (s, 3H), 3.72 (m,2H), 2.98 (td, J = 11.8, 5.2, 1H), 2.48 (td, J = 11.9, 4.2, 1H), 2.33(m, 3H), 2.12 (ddd, J = 13.5, 11.9, 5.4, 1H), 1.99 (m, 1H), 1.77 (m,2H), 1.62 (m, 1H), 1.48 (m, 4H), 1.17 (m, 1H), 0.78 (dt, J = 13.1, 8.9,1H).  

524. [(5-methyl-1H-pyrazol-3-yl)methyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine MS: 355.3 1H NMR(400 MHz, CD3CN) δ 8.78 (dd, J = 5.5, 1.2, 1H), 8.34 (td, J = 8.0, 1.7,1H), 7.79 (m, 2H), 6.07 (s, 1H), 5.95 (brs, 1H), 4.02 (m, 2H), 3.72 (m,2H), 2.97 (td, J = 12.0, 5.1, 1H), 2.44 (ddd, J = 12.1, 10.0, 4.2, 1H),2.34 (m, 3H), 2.26 (s, 3H), 2.18 (td, J = 13.1, 5.2, 1H), 2.03 (d, J =14.2, 1H), 1.81 (ddd, J = 8.7, 7.4, 3.8, 2H), 1.63 (ddd, J = 14.6,10.4,4.6, 1H), 1.49 (m, 4H), 1.20 (m, 1H), 0.81 (dt, J = 12.9, 8.9, 1H). 

525. [(1,5-dimethyl-1H-pyrazol-3-yl)methyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine MS: 369.3 1H NMR(400 MHz, CD3CN) δ 12.13 (brs, 1H), 8.77 (dd, J = 5.4, 1.2, 1H), 8.28(td, J = 8.0, 1.7, 1H), 8.00 (brs, 1H), 7.74 (m, 2H), 6.03 (s, 1H), 3.96(m, 2H), 3.73 (m, 5H), 2.96 (td, J = 12.0, 5.2, 1H), 2.47 (td, J = 12.1,4.2, 1H), 2.36 (m, 3H), 2.17 (m, 4H), 2.00 (m, 1H), 1.79 (m, 2H), 1.63(ddd, J 8.4, 7.6, 3.3, 1H), 1.50 (m, 4H), 1.19 (ddd, J = 10.1, 6.6, 1.8,1H), 0.81 (dt, J = 12.9, 8.9, 1H).  

526. (1H-pyrazol-4-ylmethyl)({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine MS: 341.2 1H NMR (400 MHz, CD3CN) δ8.73 (dd, J = 5.3, 1.1, 1H), 8.21 (td, J = 8.0, 1.7, 2H), 7.75 (d, J =8.2, 1H), 7.66 (m, 3H), 7.56 (s, 1H), 3.96 (s, 2H), 3.73 (m, 2H), 2.91(m, 1H), 2.32 (m, 4H), 2.08 (m, 1H), 1.99 (m, 1H), 1.78 (m, 2H), 1.62(m, 1H), 1.49 (m, 4H), 1.19 (m, 1H), 0.78 (dt, J = 13.1, 8.8, 1H).  

527. [(1-methyl-1H-pyrazol-4-yl)methyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine MS: 355.2 1H NMR(400 MHz, CD3CN) δ 8.78 (dd, J = 5.5, 1.3, 1H), 8.32 (td, J = 8.0, 1.7,1H), 7.84 (d, J = 8.2, 1H), 7.77 (ddd, J = 7.6, 5.5, 0.9, 1H), 7.71(brs, 1H), 7.55 (s, 1H), 7.43 (s, 1H), 3.91 (s, 2H), 3.81 (d, J = 11.7,3H), 3.73 (m, 2H), 2.90 (dt, J = 11.7,5.8, 1H), 2.35 (m, 4H), 2.14 (ddd,J = 10.8, 10.2, 5.2, 1H), 2.03 (d, J = 14.2, 1H), 1.80 (m, 2H), 1.62(tdd, J = 8.7, 6.8, 2.7, 1H), 1.49 (m, 4H), 1.20 (m, 1H), 0.80 (dt, J =12.9, 8.8, 1H).  

528. [(5-methyl-1H-pyrazol-4-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan- 9-yl]ethyl})amine

529. [(1,5-dimethyl-1H-pyrazol-4-yl)methyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

530. [(5,6-difluoropyridin-3-yl)methyl]({2-[(9R)- 9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

531. [(5-chloro-6-fluoropyridin-3-yl)methyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

532. [(5-bromo-6-fluoropyridin-3-yl)methyl]({2- [(9R)9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

533. [(6-fluoro-5-iodopyridin-3-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan- 9-yl]ethyl})amine

534. [(6-fluoro-5-methylpyridin-3-yl)methyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine MS: 384.3 1H NMR(400 MHz, CD3CN) δ 8.73 (d, J = 4.4, 1H), 8.36 (s, 1H), 8.20 (d, J = 7.81H) 8.01 (s 1H), 7.77 (t, J = 7.1, 2H), 7.66 (m, 1H), 4.01 (s, 2H), 3.73(m, 2H), 2.98 (dd, J = 11.6, 6.9, 1H), 2.36 (m, 5H), 2.26 (s, 3H), 2.16(dd, J = 13.2, 5.1, 2H), 1.80 (m, 2H), 1.51 (m, 6H), 1.20 (dd, J = 8.7,4.7, 1H), 0.79 (d, J = 13.3, 1H).  

535. [(6-fluoro-5-methoxypyridin-3- yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

536. 2-fluoro-5-[({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}amino)methyl]pyridine-3- carbonitrile

537. [(6-chloro-5-fluoropyridin-3-yl)methyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine MS: 404.2 1H NMR(400 MHz, CD3CN) δ 8.68 (dd, J = 5.2, 1.1, 1H), 8.24 (d, J = 1.9, 1H),8.10 (td, J = 7.9, 1.8, 1H), 7.78 (dd, . = 9.0, 2.0, 1H), 7.69 (d, J =8.2, 1H), 7.56 (ddd, J = 7.5, 5.3, 0.9, 1H), 4.75 (brs, 1H), 4.07 (m,2H), 3.72 (m, 2H), 2.99 (td, J = 11.9, 5.2, 1H), 2.48 (td, J = 12.0,4.5, 1H), 2.32 (m, 3H), 2.11 (m, 1H), 1.77 (m, 2H), 1.62 (m, 1H), 1.49(m, 4H), 1.17 (m, 1H), 0.77 (dt, J = 13.1, 8.9, 1H).  

538. [(5,6-dichloropyridin-3-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine MS: 422.2 1HNMR (400 MHz, CD3CN) δ 8.51 (m, 1H), 8.33 (d, J =2.1 1H) 8.12(d, J =2.11H) 7.76(t, J =7.9 1H), 7.49 (d, J = 8.1, 1H), 7.23 (dd, J = 7.4, 4.9,1H), 4.26 (d, J = 1.5, 2H), 3.57 (dd, J = 7.7, 3.0, 2H), 3.09 (td, J =12.2, 4.6, 1H), 2.55 (td, J = 12.1, 4.6, 1H), 2.27 (dddd, J = 25.5,17.3, 14.3, 3.4, 4H), 1.77 (m, 1H), 1.59 (m, 2H), 1.34 (m, 6H), 0.98(dd, J = 11.4, 5.0, 1H), 0.60 (dt, J = 13.4, 9.0, 1H).  

539. [(5-bromo-6-chloropyridin-3-yl)methyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine MS: 466.1 1H NMR(400 MHz, CD3CN) δ 8.64 (d, J = 5.1, 1H), 8.36 (d, J = 2.1, 1H), 8.24(d, J = 2.1, 1H), 8.02 (m, 1H), 7.69 (d, J = 8.0, 1H), 7.47 (m, 1H),3.59 (m, 2H), 3.17 (d, J = 4.7, 1H), 2.63 (d, J = 4.5, 1H), 2.34 (m,4H), 2.12 (d, J = 4.8, 1H), 1.85 (d, J = 13.8, 1H), 1.66 (m, 2H), 1.35(m, 6H), 1.02 (m, 1H), 0.66 (s, 1H).  

540. [(6-chloro-5-iodopyridin-3-yl)methyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

541. [(6-chloro-5-methylpyridin-3-yl)methyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine MS: 400.2 1H NMR(400 MNz, CD3CN) δ 8.70 (dd, J = 5.3, 1.2, 1H), 8.20 (t, J = 2.4, 1H),8.17 (dd, J = 7.9, 1.7, 1H), 7.74 (t, J = 5.2, 2H), 7.63 (ddd, J = 7.5,5.3, 0.9, 1H), 5.11 (s, 1H), 4.01 (m, 2H), 3.73 (m, 2H), 2.98 (td, J =11.9, 5.1, 1H), 2.46 (td, J = 12.0, 4.2, 1H), 2.33 (m, 6H), 2:12 (ddd, J= 14.7, 10.5, 5.3, 1H), 1.99 (d, J = 6.9, 1H), 1.78 (m, 2H), 1.62 (m,1H), 1.48 (m, 4H), 1.18 (m, 1H. 0.78 (dt. J = 13.1, 8.9, 1H).  

542. [(6-chloro-5-methoxypyridin-3- yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine MS: 416.2 1H NMR(400 MHz, CD3CN) δ 8.73 (dd, J 5.4, 1.2, 1H), 8.26 (td, J = 7.9, 1.6,1H), 7.93 (d, J = 1.9, 1H), 7.80 (d, J = 8.2, 1H), 7.70 (dd, J = 7.1,5.9, 1H), 7.52 (d, J = 1.9, 1H), 5.05 (brs, 1H), 4.04 (m, 2H), 3.90 (s,3H), 3.74 (m, 2H), 2.98 (td, J = 12.0, 5.1, 1H), 2.40 (dddd, J = 19.5,12.3, 9.6, 4.7, 3H), 2.16 (m, 1H), 1.99 (m, 1H), 1.80 (m, 2H), 1.63(ddd, J = 14.5, 7.2, 3.0, 1H), 1.49 (m, 4H), 1.20 (m, 1H), 0.80 (dt, J =12.9, 8.8, 1H).  

543. 2-chloro-5-[({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}amino)methyl]pyridine-3- carbonitrile

544. 3-fluoro-5-[({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}amino)methyl]pyridine-2- carbonitrile

545. 3-chloro-5-[({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl}ethyl}amino)methyl]pyridine-2- carbonitrile

546. 3-bromo-5-[({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}amino)methyl]pyridine-2- carbonitrile

547. 3-iodo-5-[({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}amino)methyl]pyridine-2- carbonitrile

548. 3-methyl-5-[({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}amino)methyl]pyridine-2- carbonitrile

549. 3-methyl-5-[({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}amino)methyl]pyridine-2- carbonitrile

550. 5-[({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}amino)methyl]pyridine-2,3- dicarbonitrile

551. 5-[({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}amino)methyl]-3- (trifluoromethyl)pyridine-2- carbonitrile

552. {[5-fluoro-6-(trifluoromethyl)pyridin-3-yl]methyl}({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine

553. {[5-chloro-6-(trifluoromethyl)pyridin-3-yl]methyl}({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine

554. {[5-bromo-6-(trifluoromethyl)pyridin-3-yl]methyl}({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine MS: 498.1 1H NMR (400 MHz, CD3CN) δ8.74 (dd, J = 5.4, 1.2, 1H), 8.64 (d, J = 1.6, 1H), 8.32 (d, J = 1.2,1H), 8.26 (td, J = 8.0, 1.6, 1H), 7.81 (d, J = 8.2, 1H), 7.71 (dd, J =7.1, 6.0, 1H), 4.12 (m, 3H), 3.74 (m, 3H), 3.00 (td, J = 12.0, 5.1, 1H),2.49 (td, J = 12.1, 4.2, 1H), 2.37 (ddd, J = 14.0, 11.9, 5.0, 3H), 2.16(m, 1H), 2.02 (m, 1H), 1.81 (m, 2H), 1.63 (ddd, J = 14.4, 8.7, 4.7, 1H),1.49 (m, 4H), 1.21 (m, 1H), 0.80 (dt, J = 13.0, 8.9, 1H).  

555. {[5-iodo-6-(trifluoromethyl)pyridin-3-yl]methyl}({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine

556. {[5-methyl-6-(trifluoromethyl)pyridin-3-yl]methyl}({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine

557. {[5-methoxy-6-(trifluoromethyl)pyridin-3-yl]methyl}({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine

558. 5-[({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}amino)methyl]-2- (trifluoromethyl)pyridine-3-carbonitrile

559. {[5,6-bis(trifluoromethyl)pyridin-3- yl]methyl}({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan- 9- yl]ethyl})amine

560. [(5-fluoro-6-methylpyridin-3-yl)methyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

561. [(5-chloro-6-methylpyridin-3-yl)methyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

562. [(5-bromo-6-methylpyridin-3-yl)methyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

563. [(5-iodo-6-methylpyridin-3-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan- 9-yl]ethyl})amine

564. [(5,6-dimethylpyridin-3-yl)methyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

565. [(5-methoxy-6-methylpyridin-3- yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

566. 2-methyl-5-[({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}amino)methyl]pyridine-3- carbonitrile

567. {[6-methyl-5-(trifluoromethyl)pyridin-3-yl]methyl}({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine

568. [(5-fluoro-6-methoxypyridin-3-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine MS: 400.3 1H NMR (400 MHz, CD3CN) δ8.63 (dd, J = 5.3, 1.2, 1H), 8.25 (s, 1H), 8.12 (td, J = 8.0, 1.6, 1H),7.83 (d, J = 1.9, 1H), 7.67 (d, J = 8.2, 1H), 7.57 (dd, J = 6.8, 5.7,1H), 7.44 (dd, J = 11.1,2.0, 1H), 3.88 (d, J = 6.7, 5H), 3.62 (m, 2H),2.86 (dd, J = 11.5, 7.1, 1H), 2.26 (m, 4H), 2.05 (dd, J = 12.7, 5.0,1H), 1.69 (ddd, J = 9.5, 8.0, 4.4, 2H), 1.69 (ddd, J = 9.5, 8.0, 4.4,2H), 1.39 (m, 5H), 0.68 (d, J = 13.3, 1H).  

569. [(5-chloro-6-methoxypyridin-3- yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine MS: 416.2 1H NMR(400 MHz, CD3CN) δ 8.65 (d, J = 5.4, 1H), 8.21 (s, 1H), 8.18 (d, J =8.0, IH), 7.96 (d, J = 2.1, 1H), 7.72 (m, 2H), 7.63 (t, J = 6.4, 1H),3.87 (m, 5H), 3.62 (m, 2H), 2.85 (dd, J = 11.5, 7.2, IH), 2.27 (m, 4H),2.07 (d, J = 4.9, 1H), 1.91 (d, J = 14.1, 1H), 1.69 (m, 2H), 1.39 (m,5H), 1.10 (m, 1H), 0.69 (d, J = 13.2, 1H).  

570. [(5-bromo-6-methoxypyridin-3- yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine MS: 460.2 1H NMR(400 MHz, CDCl3) δ 8.79 (dd, J = 5.7, 1.3, 1H), 8.43 (td, J = 8.0, 1.7,1H), 8.11 (d, J = 2.1, 1H), 7.98 (d, J = 2.1, 1H), 7.92 (d, J = 8.2,1H), 7.86 (ddd, J = 7.6, 5.7, 1.0, 1H), 5.63 (brs, 1H), 3.97 (m, 5H),3.75 (m, 2H), 2.96 (m, 1H), 2.42 (dq, J = 12.2, 4.1, 2H), 2.33 (d, J =14.1, 2H), 2.21 (m, 1H), 2.06 (d, J = 14.2, 1H), 1.83 (m, 2H), 1.64(ddd, J = 19.4, 10.1, 4.4, 1H), 1.50 (m, 4H), 1.23 (m, 1H), 0.82 (dt, J= 12.9, 8.9, 1H).  

571. [(5-iodo-6-methoxypyridin-3-yl)methyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- l]ethyl})amine

572. [(6-methoxy-5-methylpyridin-3- yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine MS: 396.3 1H NMR(400 MHz, CDCl3) δ 8.78 (dd, J = 5.6, 1.3, 1H), 8.38 (td, J = 8.0, 1.7,1H), 7.96 (d, J = 2.2, 1H), 7.88 (d, J = 8.2, 1H), 7.81 (ddd, J = 7.6,5.6, 1.0, 1H), 7.49 (d, J = 1.5, 1H), 5.36 (brs, 1H), 3.93 (m, 5H), 3.74(m, 2H), 2.95 (dd, J = 11.4, 7.7, 1H), 2.39 (m, 4H), 2.21 (dd, J = 13.2,5.4, 1H), 2.14 (m, 3H), 2.05 (d, J = 14.2, 1H), 1.82 (m, 2H), 1.63 (m,1H), 1.50 (m, 4H), 1.21 (ddd, J = 10.5, 6.1, 2.5, 1H), 0.81 (dt, J =12.9, 8.8, 1H).  

573. [(5,6-dimethoxypyridin-3-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan- 9-yl]ethyl})amine

574. 2-methoxy-5-[({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}amino)methyl]pyridine-3- carbonitrile

575. {[6-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl}({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine

Example 14 Opioid Receptor Ligands

The following compounds in Table 3 can also be prepared according to theprocedures described above from appropriate starting materials andappropriate reagents and would be expected to also have similarproperties and therapeutic effects as other compounds described herein.In addition to the specific structure shown the other isomers orenantiomers are included with the description herein. Compounds thathave been made lists NMR data and prophetic examples do not list NMRdata.

TABLE 3 Opioid Receptor Ligands Compound Name Structure 576[(5-chloropyridin-3- yl)methyl]({2-[(9R)-9-phenyl-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

577 {2-[(9R)-9-phenyl-6- oxaspiro[4.5]decan-9- yl]ethyl}({[5-(trifluoromethyl)pyridin-3- yl]methyl})amine

578 {2-[(9R)-9-phenyl-6- oxaspiro[4.5]decan-9- yl]ethyl}({[4-(trifluoromethyl)pyridin-3- yl]methyl})amine

579 [(3,5-difluorophenyl)methyl]({2- [(9R)-9-phenyl-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

580 [(3-methylphenyl)methyl]({2- [(9R)-9-phenyl-6- oxaspiro[4.5]decan-9-yl]ethyl})amine

581 [(5-chloropyridin-3- yl)methyl]({2-[(9R)-9-(4- fluorophenyl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

582 {2-[(9R)-9-(4-fluorophenyl)-6- oxaspiro[4.5]decan-9- yl]ethyl}({[5-(trifluoromethyl)pyridin-3- yl]methyl})amin

583 {2-[(9R)-9-(4-fluorophenyl)-6- oxaspiro[4.5]decan-9- yl]ethyl}({[4-(trifluoromethyl)pyridin-3- yl]methyl})amine

584 [(3,5-difluorophenyl)methyl]({2- [(9R)-9-(4- fluorophenyl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

585 [(5-chloropyridin-3- yl)methyl]({2-[(9R)-9-[4-(trifluoromethoxy)phenyl]-6- oxaspiro[4.5]decan-9- yl]ethyl})amine

586 {2-[(9R)-9-[4- (trifluoromethoxy)phenyl]-6- oxaspiro[4.5]decan-9-yl]ethyl}({[5- (trifluoromethyl)pyridin-3- yl]methyl})amine

587 {2-[(9R)-9-[4- (trifluoromethoxy)phenyl]-6- oxaspiro[4.5]decan-9-yl]ethyl}({[4- (trifluoromethyl)pyridin-3- yl]methyl})amine

588 [(3,5-difluorophenyl)methyl]({2- [(9R)-9-[4-(trifluoromethoxy)phenyl]-6- oxaspiro[4.5]decan-9- yl]ethyl})amine

589 [(3-methylphenyl)methyl]({2- [(9R)-9-[4-(trifluoromethoxy)phenyl]-6- oxaspiro[4.5]decan-9- yl]ethyl})amine

590 [(5-chloropyridin-3- yl)methyl]({2-[(9R)-9-(pyridin-3-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

591 {2-[(9R)-9-(pyridin-3-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl}({[5-(trifluoromethyl)pyridin-3- yl]methyl})amine

592 {2-[(9R)-9-(pyridin-3-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl}({[4-(trifluoromethyl)pyridin-3- yl]methyl})amine

593 [(3,5-difluorophenyl)methyl]({2- [(9R)-9-(pyridin-3-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

594 [(3-methylphenyl)methyl]({2- [(9R)-9-(pyridin-3-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

595 [(5-chloropyridin-3- yl)methyl]({2-[(9R)-9-(pyridin-4-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

596 {2-[(9R)-9-(pyridin-4-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl}({[5-(trifluoromethyl)pyridin-3- yl]methyl})amine

597 {2-[(9R)-9-(pyridin-4-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl}({[4-(trifluoromethyl)pyridin-3- yl]methyl})amine

598 [(3,5-difluorophenyl)methyl]({2- [(9R)-9-(pyridin-4-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

599 [(3-methylphenyl)methyl]({2- [(9R)-9-(pyridin-4-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

600 [(5-chloropyridin-3- yl)methyl]({2-[(9R)-9-(3- methylphenyl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

601 {2-[(9R)-9-(3-methylphenyl)-6- oxaspiro[4.5]decan-9- yl]ethyl}({[5-(trifluoromethyl)pyridin-3- yl]methyl})amine

602 {2-[(9R)-9-(3-methylphenyl)-6- oxaspiro[4.5]decan-9- yl]ethyl}({[4-(trifluoromethyl)pyridin-3- yl]methyl})amine

603 [(3,5-difluorophenyl)methyl]({2- [(9R)-9-(3- methylphenyl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

604 {2-[(9R)-9-(3-methylphenyl)-6- oxaspiro[4.5]decan-9- yl]ethyl}[(3-methylphenyl)methyl]amine

605 [(5-chloropyridin-3- yl)methyl]({2-[(9R)-9-[3-(trifluoromethoxy)phenyl]-6- oxaspiro[4.5]decan-9- yl]ethyl})amine

606 {2-[(9R)-9-[3- (trifluoromethoxy)phenyl]-6- oxaspiro[4.5]decan-9-yl]ethyl}({[5- (trifluoromethyl)pyridin-3- yl]methyl})amine

607 {2-[(9R)-9-[3- (trifluoromethoxy)phenyl]-6- oxaspiro[4.5]decan-9-yl]ethyl}({[4- (trifluoromethyl)pyridin-3- yl]methyl})amine

608 [(3,5-difluorophenyl)methyl]({2- [(9R)-9-[3-(trifluoromethoxy)phenyl]-6- oxaspiro[4.5]decan-9- yl]ethyl})amine

609 [(3-methylphenyl)methyl]({2- [(9R)-9-[3-(trifluoromethoxy)phenyl]-6- oxaspiro[4.5]decan-9- yl]ethyl})amine

610 [(5-chloropyridin-3- yl)methyl]({2-[(9R)-9-[4-(trifluoromethyl)phenyl]-6- oxaspiro[4.5]decan-9- yl]ethyl})amine

611 {2-[(9R)-9-[4- (trifluoromethyl)phenyl]-6- oxaspiro[4.5]decan-9-yl]ethyl}({[5- (trifluoromethyl)pyridin-3- yl]methyl})amine

612 {2-[(9R)-9-[4- (trifluoromethyl)phenyl]-6- oxaspiro[4.5]decan-9-yl]ethyl}({[4- (trifluoromethyl)pyridin-3- yl]methyl})amine

613 [(3,5-difluorophenyl)methyl]({2- [(9R)-9-[4-(trifluoromethyl)phenyl]-6- oxaspiro[4.5]decan-9- yl]ethyl})amine

614 [(3-methylphenyl]methyl]({2- [(9R)-9-[4- (trifluoromethyl)phenyl]-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

615 [(5-chloropyridin-3- yl)methyl]({2-[(9R)-9-(3- fluorophenyl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

616 {2-[(9R)-9-(3-fluorophenyl)-6- oxaspiro[4.5]decan-9- yl]ethyl}({[5-(trifluoromethyl)pyridin-3- yl]methyl})amine

617 {2-[(9R)-9-(3-fluorophenyl)-6- oxaspiro[4.5]decan-9- yl]ethyl}({[4-(trifluoromethyl)pyridin-3- yl]methyl})amine

618 [(3,5-difluorophenyl)methyl]({2- [(9R)-9-(3- fluorophenyl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

619 {2-[(9R)-9-(3-fluorophenyl)-6- oxaspiro[4.5]decan-9- yl]ethyl}[(3-methylphenyl)methyl]amine

620 [(5-chloropyridin-3- yl)methyl]({2-[(9R)-9-[3-(trifluoromethyl)phenyl]-6- oxaspiro[4.5]decan-9- yl]ethyl})amine

621 {2-[(9R)-9-[3- (trifluoromethyl)phenyl]-6- oxaspiro[4.5]decan-9-yl]ethyl}({[5- (trifluoromethyl)pyridin-3- yl]methyl})amine

622 {2-[(9R)-9-[3- (trifluoromethyl)phenyl]-6- oxaspiro[4.5]decan-9-yl]ethyl}({[4- (trifluoromethyl)pyridin-3- yl]methyl})amine

623 [(3,5-difluorophenyl)methyl]({2- [(9R)-9-[3-(trifluoromethyl)phenyl]-6- oxaspiro[4.5]decan-9- yl]ethyl})amine

624 [(3-methylphenyl)methyl]({2- [(9R)-9-[3- (trifluoromethyl)phenyl]-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

625 [(5-chloropyridin-3- yl)methyl](methyl){2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl}amine MS: 400.2 1H NMR (400 MHz, CD3CN) δ8.77 (dd, J = 5.6, 1.3, 1H), 8.67 (d, J = 2.0, 1H), 8.53 (s, 1H), 8.41(td, J = 8.0, 1.6, 1H), 7.93 (m, 2H), 7.85 (m, 1H), 4.18 (s, 2H), 3.76(ddd, J = 12.4, 11.3, 5.5, 2H), 3.09 (d, J = 5.1, 1H), 2.65 (s, 3H),2.55 (m, 2H), 2.33 (m, 3H), 2.08 (d, J = 14.2, 1H), 1.84 (m, 2H), 1.53(m, 5H), 1.21 (m, 1H), 0.77 (d, J = 13.2, 1H).

626 methyl({2-[(9R)-9-(pyridin-2-yl)- 6-oxaspiro[4.5]decan-9-yl]ethyl}){[5- (trifluoromethyl)pyridin-3- yl]methyl}amine MS: 434.3 1HNMR (400 MHz, CD3CN) δ 8.99 (s, 1H), 8.84 (s, 1H), 8.77 (m, 1H), 8.40(td, J = 8.0, 1.6, 1H), 8.23 (s, 1H), 7.91 (d, J = 8.2, 1H), 7.84 (dd, J= 6.9, 6.3, 1H), 4.26 (s, 2H), 3.77 (m, 2H), 3.11 (d, J = 4.8, 1H), 2.65(s, 3H), 2.57 (ddd, J = 17.4, 12.8, 8.9, 2H), 2.34 (dd, J = 19.0, 9.6,3H), 2.09 (d, J = 14.2, 1H), 1.86 (m, 2H), 1.54 (m, 5H), 1.20 (dd, J =9.5, 3.8, 1H), 0.77 (dd, J = 9.0, 4.1, 1H).

627 [(5-chloropyridin-3-yl)methyl- (2H2)] {2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl}amine MS: 388.2 1H NMR (400 MHz, CD3CN)δ 9.51 (s, 1H), 8.48 (d, J = 1.9, 1H), 8.45 (d, J = 2.3, 1H), 8.42 (ddd,J = 4.8, 1.8, 0.8, 1H), 8.06 (m, 1H), 7.64 (td, J = 7.8, 1.8, 1H), 7.33(d, J = 8.1, 1H), 7.12 (ddd, J = 7.4, 4.8, 0.7, 1H), 3.57 (m, 2H), 2.74(td, J = 12.0, 4.7, 1H), 2.21 (m, 4H), 1.96 (dt, J = 12.4, 6.1, 1H),1.76 (d, J = 13.8, 1H), 1.63 (dd, J = 9.9, 5.9, 1H), 1.40 (m, 6H), 0.95(m, 1H), 0.59 (m, 1H).

628 ({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl}){[5-(trifluoromethyl)pyridin-3- yl]methyl-(2H2)}amine MS: 422.3 1H NMR (400MHz, CD3CN) δ 9.44 (s, 1H), 8.82 (d, J = 1.9, 1H), 8.78 (d, J = 1.2,1H), 8.40 (ddd, J = 4.8, 1.8, 0.9, 1H), 8.31 (m, 1H), 7.61 (m, 1H), 7.31(m, 1H), 7.09 (ddd, J = 7.4, 4.8, 1.0, 1H), 3.57 (m, 2H), 2.74 (m, 1H),2.24 (m, 3H), 2.10 (m, 1H), 1.95 (dd, J = 12.5, 4.7, 1H), 1.75 (d, J =13.6, 1H), 1.44 (m, 7H), 0.96 (s, 1H), 0.59 (m, 1H).

629 {2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl}({[6-(trifluoromethyl)pyridin-2- yl]methyl})amine MS: 420.2 1H NMR (400 MHz,CD3CN) δ 8.70 (dd, J = 5.2, 1.1, 1H), 8.53 (brs, 1H), 8.11 (td, J = 7.9,1.7, 1H), 8.05 (t, J = 7.9, 1H), 7.80 (d, J = 7.8, 1H), 7.70 (d, J =8.2, 1H), 7.57 (ddd, J = 8.3, 7.5, 4.4, 2H), 6.58 (brs, 1H), 4.29 (m,2H), 3.73 (m, 2H), 3.09 (td, J = 11.8, 5.2, 1H), 2.60 (td, J = 11.9,4.8, 1H), 2.36 (m, 3H), 2.16 (m, 1H), 1.99 (m, 1H), 1.77 (ddd, J = 14.0,9.0, 5.1, 2H), 1.62 (m, 1H), 1.48 (m, 4H), 1.16 (ddd, J = 8.5, 7.0, 3.5,1H), 0.78 (dt, J = 13.1, 8.9, 1H).

630 {2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl}({[5-(trifluoromethyl)pyridin-2- yl]methyl})amine MS: 420.2 1H NMR (400 MHz,CD3CN) δ 8.86 (d, J = 0.8, 1H), 8.77 (dd, J = 5.4, 1.2, 1H), 8.20 (m,1H), 8.11 (dd, J = 8.3, 1.9, 1H), 7.77 (d, J = 8.2, 1H), 7.66 (ddd, J =7.6, 5.4, 0.9, 1H), 7.53 (d, J = 8.3, 1H), 4.31 (m, 2H), 3.73 (m, 2H),3.09 (td, J = 11.9, 5.4, 1H), 2.60 (td, J = 11.9, 4.6, 1H), 2.39 (m,3H), 2.21 (ddd, J = 13.6, 11.8, 5.4, 1H), 2.02 (d, J = 14.0, 1H), 1.80(ddd, J = 9.5, 8.3, 4.6, 2H), 1.63 (m, 1H), 1.49 (qdd, J = 13.9, 8.5,3.5, 4H), 1.19 (m, 1H), 0.80 (dt, J = 13.1, 8.8, 1H).

631 {2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}(pyridin-2- ylmethyl)amine MS: 352.3 1H NMR (400 MHz, CD3CN) δ10.49 (s, 1H), 8.81 (dd, J = 5.5, 1.2, 1H), 8.55 (dd, J = 3.7, 0.8, 1H),8.30 (td, J = 8.0, 1.7, 1H), 7.91 (td, J = 7.8, 1.7, 1H), 7.83 (d, J =8.2, 1H), 7.75 (ddd, J = 7.6, 5.5, 1.0, 1H), 7.45 (dd, J = 11.3, 6.5,2H), 4.24 (m, 2H), 3.73 (m, 2H), 3.06 (td, J = 12.0, 5.2, 1H), 2.57 (td,J = 12.1, 4.4, 1H), 2.39 (m, 3H), 2.24 (m, 1H), 2.04 (d, J = 14.0, 1H),1.82 (m, 2H), 1.63 (m, 1H), 1.50 (m, 4H), 1.19 (m, 1H), 0.81 (dt, J =12.9, 8.8, 1H).

632 {2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}(pyridin-3- ylmethyl)amine MS: 352.3 1H NMR (400 MHz, CD3CN) δ8.81 (s, 1H), 8.74 (m, 2H), 8.32 (d, J = 8.1, 1H), 8.26 (td, J = 8.0,1.7, 1H), 7.80 (m, 2H), 7.70 (m, 1H), 4.18 (m, 2H), 3.73 (m, 2H), 3.02(td, J = 12.0, 5.1, 1H), 2.51 (td, J = 12.1, 4.3, 1H), 2.36 (m, 3H),2.15 (m, 1H), 2.01 (d, J = 14.1, 1H), 1.80 (ddd, J = 9.8, 8.2, 4.7, 2H),1.62 (m, 1H), 1.48 (m, 4H), 1.19 (m, 1H), 0.80 (dt, J = 13.0, 8.8, 1H).

633 {2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}(pyridin-4- ylmethyl)amine MS: 352.3 IH NMR (400 MHz, CD3CN) δ8.73 (m, 3H), 8.20 (td, J = 8.0, 1.7, 1H), 7.82 (d, J = 6.5, 2H), 7.76(d, J = 8.2, 1H), 7.65 (m, 1H), 4.22 (m, 2H), 3.73 (m, 2H), 3.03 (td, J= 12.0, 5.1, 1H), 2.53 (td, J = 12.1, 4.4, 1H), 2.37 (m, 3H), 2.16 (m,1H), 2.00 (d, J = 14.2, 1H), 1.79 (m, 2H), 1.63 (ddd, J = 12.2, 8.8,4.0, 1H), 1.49 (m, 4H), 1.19 (m, 1H), 0.80 (dt, J = 13.1, 8.9, 1H).

634 (1H-imidazol-4-ylmethyl)({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine MS: 341.2 1H NMR (400 MHz, CD3CN)δ 8.75 (dd, J = 5.4, 1.2, 1H), 8.54 (d, J = 1.0, 1H), 8.22 (td, J = 8.0,1.6, 1H), 7.77 (d, J = 8.2, 1H), 7.67 (dd, J = 6.8, 5.6, 1H), 7.47 (s,1H), 4.18 (s, 2H), 3.72 (m, 2H), 2.92 (td, J = 12.1, 5.0, 1H), 2.38 (m,4H), 2.13 (m, 1H), 2.00 (m, 1H), 1.79 (m, 2H), 1.63 (m, 1H), 1.48 (m,4H), 1.19 (m, 1H), 0.82 (dt, J = 13.1, 8.9, 1H).

635 [(2-methylpyridin-4- yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine MS: 366.3 1H NMR (400 MHz,CD3CN) δ 8.71 (d, J = 1.9, 1H), 8.65 (dd, J = 5.1, 1.0, 1H), 8.18 (dd, J= 8.2, 2.1, 1H), 8.02 (td, J = 7.9, 1.8, 1H), 7.64 (d, J = 8.1, 2H),7.49 (dd, J = 6.7, 5.2, 1H), 4.13 (m, 2H), 3.71 (m, 2H), 3.00 (td, J =11.8, 5.1, 1H), 2.71 (s, 3H), 2.50 (td, J = 11.9, 4.6, 1H), 2.37 (m,2H), 2.23 (m, 1H), 2.06 (dd, J = 12.0, 5.1, 1H), 1.76 (ddt, J = 14.1,9.4, 3.8, 3H), 1.61 (dd, J = 16.6, 9.7, 1H), 1.49 (m, 4H), 1.16 (d, J =11.3, 1H), 0.76 (dt, J = 13.1, 8.9, 1H).

636 {2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl}({[2-(trifluoromethyl)pyridin-4- yl]methyl})amine MS: 420.2 1H NMR (400 MHz,CD3CN) δ 8.75 (d, J = 5.1, 2H), 8.30 (td, J = 8.1, 1.4, 1H), 7.84 (m,2H), 7.74 (m, 1H), 7.63 (d, J = 4.7, 1H), 4.13 (m, 2H), 3.73 (m, 2H),3.01 (td, J = 11.9, 5.0, 1H), 2.45 (m, 4H), 2.22 (td, J = 13.0, 5.0,1H), 2.03 (d, J = 14.1, 1H), 1.81 (m, 2H), 1.63 (m, 1H), 1.49 (m, 4H),1.21 (dd, J = 9.4, 5.1, 1H), 0.81 (dt, J = 12.8, 8.8,1H).

637 [(6-chloropyridin-3- yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine MS: 386.2 1H NMR (400 MHz,CD3CN) δ 8.69 (m, 1H), 8.38 (m, 1H), 8.12 (m, 1H), 7.81 (m, 1H), 7.70(m, 1H), 7.58 (m, 1H), 7.45 (m, 1H), 4.43 (s, 1H), 4.06 (d, J = 13.9,2H), 3.72 (m, 2H), 2.98 (td, J = 11.9, 5.1, 1H), 2.48 (td, J = 12.0,4.4, 1H), 2.32 (m, 3H), 2.10 (m, 1H), 1.98 (d, J = 2.4, 1H), 1.77 (m,2H), 1.61 (ddd, J = 15.0, 8.2, 4.0, 1H), 1.48 (m, 4H), 1.16 (ddd, J =8.7, 7.1, 4.1, 1H), 0.77 (dt, J = 13.2, 8.9, 1H).

638 [(1-methyl-1H-imidazol-2- yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine MS: 355.3 1H NMR (400 MHz, CD3CN)δ 8.71 (ddd, J = 5.3, 1.7, 0.6, 1H), 8.14 (td, J = 8.0, 1.8, 1H), 7.73(d, J = 8.2, 1H), 7.60 (ddd, J = 7.6, 5.3, 1.0, 1H), 7.43 (d, J = 1.9,1H), 7.35 (d, J = 1.9, 1H), 4.33 (s, 2H), 3.80 (m, 3H), 3.72 (ddt, J =15.3, 9.3, 3.1, 2H), 3.03 (td, J = 12.0, 4.9, 1H), 2.59 (td, J = 12.0,4.6, 1H), 2.36 (m, 3H), 2.15 (m, 1H), 1.99 (m, 1H), 1.80 (m, 2H), 1.63(ddd, J = 14.4, 9.9, 5.5, 1H), 1.49 (m, 4H), 1.19 (m, 1H), 0.83 (dt, J =13.1, 8.9, 1H).

639 (naphthalen-2-ylmethyl)({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine MS: 401.3 1H NMR (400 MHz, CD3CN)δ 8.57 (dd, J = 5.0, 1.0, 1H), 7.90 (m, 5H), 7.59 (m, 2H), 7.54 (d, J =8.1, 1H), 7.48 (dd, J = 8.5, 1.7, 1H), 7.34 (m, 1H), 4.19 (s, 2H), 3.69(dt, J = 8.9, 5.1, 3H), 3.48 (brs, 1H), 3.02 (s, 1H), 2.52 (s, 1H), 2.33(m, 2H), 2.19 (m, 1H), 2.02 (m, 1H), 1.89 (t, J = 9.4, 1H), 1.70 (dq, J= 9.2, 5.1, 2H), 1.59 (m, 1H), 1.44 (m, 4H), 1.10 (m, 1H), 0.69 (dt, J =13.1, 8.8, 1H).

640 [(6-bromo-5-fluoropyridin-3- yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine MS: 448.2 1H NMR (400 MHz,CD3CN) δ 8.68 (dd, J = 5.2, 1.2, 1H), 8.24 (d, J = 1.5, 1H), 8.12 (td, J= 7.9, 1.7, 1H), 7.71 (m, 2H), 7.58 (dd, J = 7.1, 5.7, 1H), 4.88 (s,1H), 4.08 (d, J = 14.0, 2H), 3.72 (m, 2H), 2.98 (td, J = 11.9, 5.1, 1H),2.48 (td, J = 12.0, 4.4, 1H), 2.32 (m, 3H), 2.11 (m, 1H), 1.98 (d, J =2.5, 1H), 1.77 (m, 2H), 1.61 (m, 1H), 1.48 (m, 4H), 1.17 (m, 1H), 0.77(dt, J = 13.1, 8.9, 1H).

641 [(5-methanesulfonylpyridin-3- yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine MS: 430.2 1H NMR (400 MHz,CD3CN) δ 9.10 (d, J = 2.0, 1H), 8.87 (d, J = 1.8, 1H), 8.71 (dd, J =5.3, 1.1, 1H), 8.37 (t, J = 2.0, 1H), 8.18 (td, J = 8.0, 1.8, 1H), 7.75(d, J = 8.2, 1H), 7.63 (ddd, J = 7.6, 5.4, 0.9, 1H), 4.16 (m, 2H), 3.73(m, 2H), 3.14 (s, 3H), 3.02 (td, J = 12.0, 5.2, 1H), 2.52 (m, 1H), 2.33(m, 3H), 2.14 (m, 1H), 2.01 (m, 1H), 1.79 (m, 2H), 1.62 (m, 1H), 1.48(m, 4H), 1.19 (m, 1H), 0.79 (dt, J = 13.1, 8.9, 1H).

642 [2-(3-methylphenyl)ethyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

643 [2-(3-chlorophenyl)ethyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

644 [2-(3-bromophenyl)ethyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

645 [2-(3-fluorophenyl)ethyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

646 {2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl}({2-[3-(trifluoromethyl)phenyl]ethyl}) amine

647 [2-(3-methoxyphenyl)ethyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

648 [2-(4-methylphenyl)ethyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

649 [2-(4-chlorophenyl)ethyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

650 [2-(4-bromophenyl)ethyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

651 [2-(4-fluorophenyl)ethyl]({2-[(9R)- 9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

652 {2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl}({2-[4-(trifluoromethyl)phenyl]ethyl}) amine

653 [2-(4-methoxyphenyl)ethyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

654 [2-(2-methylphenyl)ethyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

655 [2-(2-chlorophenyl)ethyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

656 [2-(2-bromophenyl)ethyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

657 [2-(2-fluorophenyl)ethyl]({2-[(9R)- 9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

658 {2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl}({2-[2-(trifluoromethyl)phenyl]ethyl}) amine

659 [2-(2-methoxyphenyl)ethyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

Example 15 Synthesis of[(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine(Compound 140) Methyl 2-cyano-2-[6-oxaspiro[4.5]decan-9-ylidene]acetate(mixture of E and Z isomers)

A mixture of 6-oxaspiro[4.5]decan-9-one (13.74 g, 89.1 mmol),methylcyanoacetate (9.4 ml, 106.9 mmol), ammonium acetate (1.79 g, 26.17mmol) and acetic acid (1.02 ml, 17.8 mmol) in benzene (75 ml) was heatedat reflux in a 250 ml round bottom flask equipped with a Dean-Stark anda reflux condenser. After 3 h, TLC (25% EtOAc in hexane, PMA stain)showed the reaction was completed. After cooling, benzene (50 ml) wasadded and the layer was separated, the organic was washed by water (120ml) and the aqueous layer was extracted by CH₂Cl₂ (3×120 ml). Thecombined organic was washed with sat'd NaHCO₃, brine, dried andconcentrated and the residual was purified by flash chromatography (340g silica gel column, eluted by EtOAc in hexane: 5% EtOAc, 2 CV; 5-25%,14 CV; 25-40%, 8 CV) gave a mixture of E and Z isomers: methyl2-cyano-2-[6-oxaspiro[4.5]decan-9-ylidene]acetate (18.37 g, 87.8% yield,m/z 236.0 [M+H]⁺ observed) as a clear oil.

Methyl 2-cyano-2-[9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetate

A solution of 2-bromopyridine (14.4 ml, 150 mmo) in THF (75 ml) wasadded dropwise to a solution of isopropylmagnesium chloride (75 ml, 2Min THF) at 0° C. under N₂, the mixture was then stirred at rt for 3 h,copper Iodide (2.59 g, 13.6 mmol) was added and allowed to stir at rtfor another 30 min before a solution of a mixture of E and Z isomers ofmethyl 2-cyano-2-[6-oxaspiro[4.5]decan-9-ylidene]acetate (16 g, 150mmol) in THF (60 ml) was added in 30 min. The mixture was then stirredat rt for 18 h. The reaction mixture was poured into a 200 g ice/2 N HCl(100 ml) mixture. The product was extracted with Et₂O (3×300 ml), washedwith brine (200 ml), dried (Na₂SO₄) and concentrated. The residual waspurified by flash chromatography (100 g silica gel column, eluted byEtOAc in hexane: 3% 2 CV; 3-25%, 12 CV; 25-40% 6 CV gave methyl2-cyano-2-[9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetate (15.44 g,72% yield, m/z 315.0 [M+H]+ observed) as an amber oil.

2-[9-(Pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetonitrile

Ethylene glycol (300 ml) was added to methyl2-cyano-2-[9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetate (15.43 g,49 mmol) followed by potassium hydroxide (5.5 g, 98 mmol), the resultingmix was heated to 120° C., after 3 h, the reaction mix was cooled andwater (300 ml) was added, the product was extracted by Et2O (3×400 ml),washed with water (200 ml), dried (Na2SO4) and concentrated, theresidual was purified by flash chromatography (340 g silica gel column,eluted by EtOAc in hexane: 3% 2 CV; 3-25%, 12 CV; 25-40% 6 CV to give2-[9-(Pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetonitrile (10.37 g, 82%yield, m/z 257.0 [M+H]+ observed).

2-[(9R)-9-(Pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetonitrile

The racemic 2-[9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetonitrilewas separated by chiral HPLC column under the following preparative-SFCconditions: Instrument: SFC-80 (Thar, Waters); Column: Chiralpak AD-H(Daicel); column temperature: 40° C.; Mobile phase: Methanol/CO2=40/60;Flow: 70 g/min; Back pressure: 120 Bar; Cycle time of stack injection:6.0 min; Load per injection: 225 mg; Under these conditions,2-[9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetonitrile (4.0 g) wasseparated to provide the desired isomer,2-[(9R)-9-(Pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetonitrile (2.0g, >99.5% enantiomeric excess) as a slow-moving fraction. The absolute(R) configuration of the desired isomer was later determined by an X-raycrystal structure analysis of Compound 140.

2-[(9R)-9-(Pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethan-1-amine

LAH (1M in Et2O, 20 ml, 20 mmol) was added to a solution of2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetonitrile (2.56 g,10 mmol) in Et2O (100 ml, 0.1M) at 0° C. under N₂. The resulting mix wasstirred and allowed to warm to room temperature. After 2 h, LCMS showedthe reaction had completed. The reaction was cooled at 0° C. andquenched with water (1.12 ml), NaOH (10%, 2.24 ml) and another 3.36 mlof water. Solid was filtered and filter pad was washed with ether (3×20ml). The combined organic was dried and concentrated to give2-[(9R)-9-(Pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethan-1-amine (2.44g, 94% yield, m/z 260.6 [M+H]+ observed) as a light amber oil.

Alternatively,2-[(9R)-9-(Pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethan-1-amine wasprepared by Raney-Nickel catalyzed hydrogenation.

An autoclave vessel was charged with2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4,5]decan-9-yl]acetonitrile andammonia (7N solution in methanol). The resulting solution was stirred atambient conditions for 15 minutes and treated with Raney 2800 Nickel,slurried in water. The vessel was pressurized to 30 psi with nitrogenand agitated briefly. The autoclave was vented and the nitrogen purgerepeated additional two times. The vessel was pressurized to 30 psi withhydrogen and agitated briefly. The vessel was vented and purged withhydrogen two additional times. The vessel was pressurized to 85-90 psiwith hydrogen and the mixture was warmed to 25-35° C. The internaltemperature was increased to 45-50° C. over 30-60 minutes. The reactionmixture was stirred at 45-50° C. for 3 days. The reaction was monitoredby HPLC. Once reaction was deemed complete, it was cooled to ambienttemperature and filtered through celite. The filter cake was washed withmethanol (2×). The combined filtrates were concentrated under reducedpressure at 40-45° C. The resulting residue was co-evaporated with EtOH(3×) and dried to a thick syrupy of2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethan-1-amine.

[(3-Methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine

Into a vial were added2-[(9R)-9-(Pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethan-1-amine (500mg, 1.92 mmole), 18 mL CH2Cl2 and sodium sulfate (1.3 g, 9.6 mmole). The3-methoxythiophene-2-carboxaldehyde (354 mg, 2.4 mmole) was then added,and the mixture was stirred overnight. NaBH4 (94 mg, 2.4 mmole) wasadded to the reaction mixture, stirred for 10 minutes, and then MeOH(6.0 mL) was added, stirred 1 h, and finally quenched with water. Theorganics were separated off and evaporated. The crude residue waspurified by a Gilson prep HPLC. The desired fractions collected andconcentrated and lyophilized. After lyophilization, residue waspartitioned between CH₂Cl₂ and 2N NaOH, and the organic layers werecollected. After solvent was concentrated to half of the volume, 1.0 eqof 1N HCl in Et2O was added, and majority of solvent evaporated underreduced pressure. The solid obtained was washed several times with Et2Oand dried to provide[(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})aminemonohydrochloride (336 mg, 41% yield, m/z 387.0 [M+H]+ observed) as awhite solid. The NMR for Compound 140 is described herein.

Example 16 Biological Example Procedure for the Testing forAntinociception

The hot plate assay is adapted from the procedure originally describedby O'Callaghan and Holtzman (JPET, 192, 497, 1975) and is commonly usedto determine the potential analgesic efficacy of opioid agonists. Theantinociceptive effect of the composition(s) described herein in the hotplate is expressed in % MPE (Maximum Possible Effect).

Rats (175-250 g) or mice (20-30 g) acclimated to the vivarium for atleast 48 hr prior to behavioral testing. Test drugs were administered bythe subcutaneous (SC) route. Animals were placed on the hot plate, whichthe temperature was set at 50-56° C., depending on the in vitro potencyof the compound. A cutoff time of 30-60 seconds was used depending onthe temperature of the hot plate so that the paws of the animaldisplaying analgesia, was not damaged by the heat stimulus. The cutofftime was considered a 100% response to the thermal insult. Prior to drugtreatment, each animal was tested to determine the baseline response.Thirty minutes after drug administration, animals were re-tested. Doseresponse experiments were performed to evaluate the potency of the testcompound when various doses were administered at the point when maximalanalgesia is observed.

The % MPE was calculated according to the following formula: %MPE=[(Post drug latency−baseline latency)/(60 or 30−baselinelatency)]×100

ED₅₀ values were calculated from the mean % MPE values for each groupusing log dose-response curves by least-squares regression analysis.

TABLE 4 COMPOUND ED50 or % MPE Morphine 3.8 mg/kg SC Compound 81 100% at10 mg/kg SC Compound 122 1.1 mg/kg SC Compound 28 1.2 mg/kg SC Compound145 5.9 mg/kg SC

Results are shown in Table 4. Naïve or control mice typically exhibitreaction times in the hot plate from 10-15 seconds. The ED50 formorphine in the mouse hot plate was 3.8 mg/kg with full efficacyobserved at a dose of 10 mg/kg SC. For comparison, Compound 122 andCompound 28 produced potent efficacy with an ED50 of 1.1 and 1.2 mg/kgSC, respectively. These results demonstrate that Compound 122 andCompound 28 produced a more robust analgesic effect in the mouse hotplate assay compared to morphine.

Example 17 In Vivo Administration to Humans (Prophetic Example)

One or more compounds will be administered in dosage range from 0.15 mgto 4 mg to human subject. The compound(s) will be administered as acontinuous infusion over one hour. The dose may be escalated as deemedappropriate to obtain pain relief. Dose escalation will usually notexceed 5-fold as compared to the previous dose. Dosage amounts, however,may be repeated or decreased as deemed appropriate. The subjects will betested for their ability to withstand or not appreciate pain as comparedto a control (placebo) group.

The cold pain test has been shown to be a reproducible and sensitivemeasure of the effect of opiates and other centrally acting drugs (Van Fand Rolan P E. The utility of the cold pain test to measure analgesiafrom intravenous morphine. Br. J. Clin. Pharmacol. 1996; 42: 663-664;Posner J. Pain Models in Healthy Volunteers. In: Nimmo W S, Tucker G,eds. Clinical Measurement in Drug Evaluation. 1991, Wolfe PublishingLimited, UK.; Wotherspoon H A, Kenny G N C, McArdle C S. AnalgesicEfficacy of Controlled-Release DihydroCodeine. Anaesthesia 1991; 46:915-917.; Lamb R J, Mercer A J, Posner J. The effect of lamotrigine (300mg) and dipipanone (4 mg and 8 mg), alone and in combination, on thecold-pain test in healthy volunteers. Br. J. Clin. Pharmacol. 1994; 39:539-588P.). In the test a subject's hand is immersed in cold waterchilled to a range of 1 to 3° C. The initial sensation of cold isreplaced by a deep burning discomfort in the hand which is mediated bynociceptors in veins. The discomfort gradually builds to a plateau overapproximately 90 seconds and then either persists or decreases slightly.The stimulus is easily controlled and the response is reproducible. Thetechnique has been shown to be sensitive to different doses of analgesicdrugs.

During the cold pain test, the subject will sit down and place his/hernon-dominant hand into a stirred, thermostatically controlled water bathat about 2° C. With the other hand the subject can adjust a visualanalogue scale on a computer screen using the arrow keys on the keypad.The scale is labelled “no pain” at one end and “maximum pain” at theother end. The pointer will initially be at the “no pain” end and thesubject will move the pointer across the line to rate their feelingscontinuously over the test period. At the end of 2 minutes the computerwill automatically instruct the subject to remove his/her hand which canthen be dried. The cold pain test has been used extensively in healthyvolunteer studies and is non-invasive.

It is expected that the administration of the compound(s) will enablethe human subject to feel no pain or less pain as compared to thecontrol group.

While the compounds described herein have been described with referenceto examples, those skilled in the art recognize that variousmodifications may be made without departing from the spirit and scopethereof.

All of the above U.S. patents, U.S. patent application publications,U.S. patent applications, foreign patents, foreign patent applicationsand non-patent publications referred to in this specification and/orlisted in the Application Data Sheet are incorporated herein byreference, in their entirety.

1-75. (canceled)
 76. A compound having a structure of Formula VI:

wherein: R₂₁ and R₂₂ are independently H or CH₃; A₄ is an optionallysubstituted cycle of the formula C(CH₂)_(n), where n=2-5; B₃ is H or anoptionally substituted alkyl; B₄ is C₁-C₆ alkyl; D₁ is an optionallysubstituted aryl; and B₅ is an optionally substituted aryl.
 77. Thecompound of claim 76, wherein the compound has a structure of:

wherein R₂₆ and R₂₇ are independently H or an isotope thereof.
 78. Thecompound of claim 77, wherein the compound has a structure of FormulaVII


79. The compound of claim 77, wherein the compound has a structure ofFormula VIII


80. The compound of claim 77, wherein the compound has a structure ofFormula IX


81. The compound of claim 76, wherein D1 is an optionally substitutedphenyl or an optionally substituted pyridyl.
 82. The compound of claim76, wherein B₅ is an optionally substituted heteroaryl.
 83. The compoundof claim 76, wherein B₅ is an optionally substituted aryl selected fromthe group consisting of


84. The compound of claim 76, wherein B5 is an optionally substitutedaryl selected from the group consisting of

wherein R₂₃, R₂₄, and R₃₀ are each independently null, H, OH, cycle,aryl, branched or unbranched alkyl alcohol, halo, branched or unbranchedalkyl, amide, cyano, alkoxy, haloalkyl, alkylsulfonyl, nitrite,alkylsulfanyl; or, R₂₃ and R₂₄ together form a aryl or cycle that isattached to one or more of the atoms of B₅; and R25 is H or anoptionally substituted branched or unbranched alkyl.
 85. The compound ofclaim 83, wherein R₂₃, R₂₄, and R₃₀ are each independently H, NH₂, OH,Cl, Br, F, I, OMe, CN, CH₃, phenyl, C₃-C₆ carbocycle, methanesulfonyl,CF₃,

wherein R₂₉ is H or an optionally substituted branched or unbranchedalkyl.
 86. The compound of claim 84, wherein B₅ is


87. The compound of claim 84, wherein B₅ is


88. The compound of claim 87, wherein R₂₃ is alkoxy.
 89. The compound ofclaim 88, wherein R₂₄ is H.
 90. The compound of claim 87, wherein R₂₃ ismethoxy.
 91. The compound of claim 76, wherein B₃ is H or C₁-C₅ alkyl.92. The compound of claim 76, having the structure


93. A pharmaceutical composition comprising a compound of claim 76 andpharmaceutically acceptable carrier.
 94. The pharmaceutical compositionof claim 93 further comprising at least one additional analgesic ornon-opioid analgesic.
 95. The pharmaceutical composition of claim 93further comprising at least one additional anti-constipation agent. 96.A method of treating pain comprising administering to a subject or asubject in need thereof a compound of claim
 76. 97. A method of treatingpain comprising administering to a subject or a subject in need thereofa compound of claim
 80. 98. A method of treating pain comprisingadministering to a subject or a subject in need thereof a compound ofclaim
 92. 99. The method of claim 96, wherein the compound isco-administered simultaneously or sequentially with an additionalanalgesic or non-opioid analgesic.
 100. The method of claim 96, whereinthe compound is co-administered simultaneously or sequentially with ananti-constipation agent.
 101. A process of preparing a compound of claim77, wherein R₂₆ and R₂₇ are H, the process comprising: contacting

with

under suitable conditions to form a compound having the structure of